Compounds and method for treatment of cancer

ABSTRACT

The present invention is directed to methods of use of a compound of Formula I: 
     
       
         
         
             
             
         
       
     
     and/or a pharmaceutically-acceptable salt, hydrate, solvate, tautomer, optical isomer, or combination thereof, a composition comprising the thiosemicarbazone, a method of administration thereof, and use thereof to treat a cancer.

STATEMENT OF RELATED APPLICATIONS

The present application is a continuation of pending U.S. applicationSer. No. 13/190,230 filed on Jul. 25, 2011, which is a divisional ofU.S. application Ser. No. 12/013,079, filed Jan. 11, 2008, (now U.S.Pat. No. 8,034,815), which claims the benefit of U.S. provisionalapplication U.S. Ser. No. 60/884,489, filed Jan. 11, 2007, which alsoclaims benefit of U.S. provisional application U.S. Ser. No. 60/884,504,filed Jan. 11, 2007, each of which are incorporated herein by referencein their entireties.

FIELD OF THE INVENTION

The present invention relates generally to compounds, compositions andmethods for treatment of cancer.

BACKGROUND OF THE INVENTION

Cancer, irrespective of its pathogenesis, is characterized byuncontrolled growth and survival of cells. Common to most forms ofcancer is an error in the cellular mechanism responsible for balancingcell survival and cell death.

According to the American Cancer Society, lung cancer is the leadingcause of cancer death for both men and women. Small cell lung cancer(SCLC) accounts for approximately 20% of all lung cancers. The 5-yearsurvival rate for small cell lung cancer is about 15%.

Certain thiosemicarbazones, such as those disclosed in British PatentNo. 1,026,401, International Patent Application No. WO2004/066725,Japanese Patent No. 56-95161 and U.S. Pat. No. 4,927,843, have been usedto treat, for example, a variety of viruses. Other thiosemicarbazones,however, may be used to treat cancer. French Patent No. 2,879,194 isdirected to certain thiosemicarbazones that may be used in the treatmentor prevention of cancer, in dermatological treatment, in the treatmentof cardiovascular and immune diseases, lipid-metabolism related diseasesand modulate PPAR's. International Patent Application No. WO 2006/009765is directed to specific thiosemicarbazones that may be used inanti-cancer therapy that mitigates the development of drug resistance.U.S. Pat. No. 4,593,027 is directed to hydrazone derivatives that may beused as a chemotherapeutic.

There is a need, however, for new therapeutic drug treatments to treatcancers more efficiently, and lung cancer in particular. Currenttreatment regimes for small cell lung cancer involve surgery, radiationand chemotherapy. While timely surgery can be curative, new therapiesare necessary when timely surgery is not an option.

All patents and patent applications referenced herein are incorporatedby reference herein in their entireties.

SUMMARY OF THE INVENTION

In accordance with an aspect, there is provided a compound of Formula I:

and/or a pharmaceutically-acceptable salt, hydrate, solvate, tautomer,optical isomer, or combination thereof; wherein:

R₁ and R₂ together form a substituted or unsubstituted polycyclic ringcomprising at least two ring systems, said at least two ring systemscomprising a first ring system bonded to C1 and a second ring systemfused to the first ring system, wherein:

the first ring system is a substituted or unsubstituted aromatic group,the second ring system is a substituted or unsubstituted aromatic group,a substituted or unsubstituted heteroaromatic group, a substituted orunsubstituted carbocyclic group, or a substituted or unsubstitutedheterocyclic group; or

the first ring system is a substituted or unsubstituted heteroaromaticgroup, the second ring system is a substituted or unsubstituted aromaticgroup, a substituted or unsubstituted heteroaromatic group, asubstituted or unsubstituted carbocyclic group, or a substituted orunsubstituted heterocyclic group; or

the first ring system is a substituted or unsubstituted saturatedcarbocyclic group, the second ring system is a substituted orunsubstituted aromatic group, a substituted or unsubstituted unsaturatedcarbocyclic group, a substituted or unsubstituted heterocyclic group, ora substituted or unsubstituted ring B:

wherein X₁ to X₆ are each independently selected from carbon or aheteroatom; or

the first ring system is a substituted or unsubstituted unsaturatedcarbocyclic group, the second ring system is a substituted orunsubstituted aromatic group, a substituted or unsubstituted carbocyclicgroup, a substituted or unsubstituted heterocyclic group, or asubstituted or unsubstituted ring B:

wherein X₁ to X₆ are each independently selected from carbon or aheteroatom; or

the first ring system is a substituted or unsubstituted heterocyclicgroup, the second ring system is a substituted or unsubstitutedheteroaromatic group, a substituted or unsubstituted carbocyclic group,or a substituted or unsubstituted heterocyclic group; and

R₃ to R₁₁ are each independently selected from H, a substituted orunsubstituted hydrocarbon group, a substituted or unsubstitutedheterogeneous group, a substituted or unsubstituted carbocyclic group, asubstituted or unsubstituted heterocyclic group, substituted orunsubstituted aromatic, or a substituted or unsubstitutedheteroaromatic;

R₁₂ is selected from H or a hydrocarbyl group;

Y is selected from a heteroatom or a carbon atom;

A is selected from a substituted or unsubstituted hydrocarbon group, asubstituted or unsubstituted heterogeneous group, a substituted orunsubstituted carbocyclic group, a substituted or unsubstitutedheterocyclic group, substituted or unsubstituted aromatic, or asubstituted or unsubstituted heteroaromatic; and

n is an integer.

In a further aspect, there is provided a composition comprising thecompound of Formula I.

In another aspect, there is provided a method of administration of thecompound of Formula I or composition thereof to treat a cancer.

In yet another aspect, there is provided use of the compound of FormulaI or composition thereof to treat a cancer.

Other features and advantages of the present invention will becomeapparent from the following detailed description. It should beunderstood, however, that the detailed description and the specificexamples while indicating embodiments of the invention are given by wayof illustration only, since various changes and modifications within thespirit and scope of the invention will become apparent to those skilledin the art from the detailed description.

BRIEF DESCRIPTION OF THE DRAWINGS

Embodiments of the present invention will now be described, by way ofexample only, with reference to the attached Figures.

FIG. 1 shows the volume of SHP77 human SCLC tumour in nude mice treatedwith test compounds;

FIG. 2 shows number of SHP77 human SCLC tumours in nude mice treatedwith test compounds;

FIG. 3 shows the volume of N417 human SCLC tumour in nude mice treatedwith COTI-2 and control;

FIG. 4 shows lack of emerging resistance in DMS153 cells treated withCOTI-2 and COTI-219;

FIG. 5 lack of emerging resistance in SHP77 cells treated with COTI-2and COTI-219;

FIGS. 6A and 6B show volume of U87 human glioma tumours in nude micetreated with two different concentrations of COTI-2; and

FIG. 7 shows Western blot analysis of cellular lysates of SHP77 cellsthat have been treated with COTI-2.

DETAILED DESCRIPTION

The present invention is directed to a thiosemicarbazone, a compositioncomprising the thiosemicarbazone, a method of administration thereof,and use thereof to treat a cancer.

Definitions

When describing the compounds, compositions, methods and uses of thisinvention, the following terms have the following meanings unlessotherwise indicated.

The term “therapeutically effective amount” as used herein means thatamount of active compound or pharmaceutical agent that elicits thebiological or medicinal response in a tissue, system, animal or humanthat is being sought by a researcher, veterinarian, medical doctor orother clinician.

The compounds of the present invention may have asymmetric centers,chiral axes, and chiral planes (as described, for example, in: E. L.Eliel and S. H. Wilen, Stereo-chemistry of Carbon Compounds, John Wiley& Sons, New York, 1994, pages 1119-1190), and occur as racemates,racemic mixtures, and as individual diastereomers, with all possibleisomers and mixtures thereof, including optical isomers, being includedin the present invention. In addition, the compounds disclosed hereinmay exist as tautomers and both tautomeric forms are intended to beencompassed by the scope of the invention, even though only onetautomeric structure may be depicted.

Generally, reference to a certain element such as hydrogen or H is meantto, if appropriate, include all isotopes of that element.

Where the term “alkyl group” is used, either alone or within other termssuch as “haloalkyl group” and “alkylamino group”, it encompasses linearor branched carbon radicals having, for example, one to about twentycarbon atoms or, in specific embodiments, one to about twelve carbonatoms. In other embodiments, alkyl groups are “lower alkyl” groupshaving one to about six carbon atoms. Examples of such groups include,but are not limited thereto, methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl andthe like. In more specific embodiments, lower alkyl groups have one tofour carbon atoms.

The term “alkenyl group” encompasses linear or branched carbon radicalshaving at least one carbon-carbon double bond. The term “alkenyl group”can encompass conjugated and non-conjugated carbon-carbon double bondsor combinations thereof. An alkenyl group, for example and without beinglimited thereto, can encompass two to about twenty carbon atoms or, in aparticular embodiment, two to about twelve carbon atoms. In embodiments,alkenyl groups are “lower alkenyl” groups having two to about fourcarbon atoms. Examples of alkenyl groups include, but are not limitedthereto, ethenyl, propenyl, allyl, propenyl, butenyl and4-methylbutenyl. The terms “alkenyl group” and “lower alkenyl group”,encompass groups having “cis” and “trans” orientations, oralternatively, “E” and “Z” orientations.

The term “alkynyl group” denotes linear or branched carbon radicalshaving at least one carbon-carbon triple bond. The term “alkynyl group”can encompass conjugated and non-conjugated carbon-carbon triple bondsor combinations thereof. Alkynyl group, for example and without beinglimited thereto, can encompass two to about twenty carbon atoms or, in aparticular embodiment, two to about twelve carbon atoms. In embodiments,alkynyl groups are “lower alkynyl” groups having two to about ten carbonatoms. Some examples are lower alkynyl groups having two to about fourcarbon atoms. Examples of such groups include propargyl, butynyl, andthe like.

The term “halo” means halogens such as fluorine, chlorine, bromine oriodine atoms.

The term “haloalkyl group” encompasses groups wherein any one or more ofthe alkyl carbon atoms is substituted with halo as defined above.Specifically encompassed are monohaloalkyl, dihaloalkyl andpolyhaloalkyl groups including perhaloalkyl. A monohaloalkyl group, forone example, may have either an iodo, bromo, chloro or fluoro atomwithin the group. Dihalo and polyhaloalkyl groups may have two or moreof the same halo atoms or a combination of different halo groups. “Lowerhaloalkyl group” encompasses groups having 1-6 carbon atoms. In someembodiments, lower haloalkyl groups have one to three carbon atoms.Examples of haloalkyl groups include fluoromethyl, difluoromethyl,trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl,pentafluoroethyl, heptafluoropropyl, difluorochloromethyl,dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl anddichloropropyl.

The term “hydroxyalkyl group” encompasses linear or branched alkylgroups having, for example and without being limited thereto, one toabout ten carbon atoms, any one of which may be substituted with one ormore hydroxyl groups. In embodiments, hydroxyalkyl groups are “lowerhydroxyalkyl” groups having one to six carbon atoms and one or morehydroxyl groups. Examples of such groups include hydroxymethyl,hydroxyethyl, hydroxypropyl, hydroxybutyl and hydroxyhexyl.

The term “alkoxy group” encompasses linear or branched oxy-containinggroups each having alkyl portions of, for example and without beinglimited thereto, one to about ten carbon atoms. In embodiments, alkoxygroups are “lower alkoxy” groups having one to six carbon atoms.Examples of such groups include methoxy, ethoxy, propoxy, butoxy andtert-butoxy. In certain embodiments, lower alkoxy groups have one tothree carbon atoms. The “alkoxy” groups may be further substituted withone or more halo atoms, such as fluoro, chloro or bromo, to provide“haloalkoxy” groups. In other embodiments, lower haloalkoxy groups haveone to three carbon atoms. Examples of such groups includefluoromethoxy, chloromethoxy, trifluoromethoxy, trifluoroethoxy,fluoroethoxy, and fluoropropoxy.

The term “aromatic group” or “aryl group” means an aromatic group havingone or more rings wherein such rings may be attached together in apendent manner or may be fused. In particular embodiments, an aromaticgroup is one, two or three rings. Monocyclic aromatic groups may contain4 to 10 carbon atoms, typically 4 to 7 carbon atoms, and more typically4 to 6 carbon atoms in the ring. Typical polycyclic aromatic groups havetwo or three rings. Polycyclic aromatic groups having two ringstypically have 8 to 12 carbon atoms, preferably 8 to 10 carbon atoms inthe rings. Examples of aromatic groups include, but are not limited to,phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthryl,anthryl or acenaphthyl.

The term “heteroatom” means an atom other than carbon. Typically,heteroatoms are selected from the group consisting of sulfur,phosphorous, nitrogen and oxygen atoms. Groups containing more than oneheteroatom may contain different heteroatoms.

The term “heteroaromatic group” or “heteroaryl group” means an aromaticgroup having one or more rings wherein such rings may be attachedtogether in a pendent manner or may be fused, wherein the aromatic grouphas at least one heteroatom. Monocyclic heteroaromatic groups maycontain 4 to 10 member atoms, typically 4 to 7 member atoms, and moretypically 4 to 6 member atoms in the ring. Typical polycyclicheteroaromatic groups have two or three rings. Polycyclic aromaticgroups having two rings typically have 8 to 12 member atoms, moretypically 8 to 10 member atoms in the rings. Examples of heteroaromaticgroups include, but are not limited thereto, pyrrole, imidazole,thiazole, oxazole, furan, thiophene, triazole, pyrazole, isoxazole,isothiazole, pyridine, pyrazine, pyridazine, pyrimidine, triazine,indole, benzofuran, benzothiophene, benzimidazole, benzthiazole,quinoline, isoquinoline, quinazoline, quinoxaline and the like.

The term “carbocyclic group” means a saturated or unsaturatedcarbocyclic hydrocarbon ring. Carbocyclic groups are not aromatic.Carbocyclic groups are monocyclic or polycyclic. Polycyclic carbocyclicgroups can be fused, spiro, or bridged ring systems. Monocycliccarbocyclic groups may contain 4 to 10 carbon atoms, typically 4 to 7carbon atoms, and more typically 5 to 6 carbon atoms in the ring.Bicyclic carbocyclic groups may contain 8 to 12 carbon atoms, typically9 to 10 carbon atoms in the rings.

The term “heterocyclic group” means a saturated or unsaturated ringstructure containing carbon atoms and 1 or more heteroatoms in the ring.Heterocyclic groups are not aromatic. Heterocyclic groups are monocyclicor polycyclic. Polycyclic heterocyclic groups can be fused, spiro, orbridged ring systems. Monocyclic heterocyclic groups may contain 4 to 10member atoms (i.e., including both carbon atoms and at least 1heteroatom), typically 4 to 7, and more typically 5 to 6 in the ring.Bicyclic heterocyclic groups may contain 8 to 18 member atoms, typically9 or 10 member atoms in the rings. Representative heterocyclic groupsinclude, by way of example, pyrrolidine, imidazolidine, pyrazolidine,piperidine, 1,4-dioxane, morpholine, thiomorpholine, piperazine,3-pyrroline and the like.

The term “heterogeneous group” means a saturated or unsaturated chain ofnon-hydrogen member atoms comprising carbon atoms and at least oneheteroatom. Heterogeneous groups typically have 1 to 25 member atoms.More typically, the chain contains 1 to 12 member atoms, 1 to 10, andmost typically 1 to 6. The chain may be linear or branched. Typicalbranched heterogeneous groups have one or two branches, more typicallyone branch. Typically, heterogeneous groups are saturated. Unsaturatedheterogeneous groups may have one or more double bonds, one or moretriple bonds, or both. Typical unsaturated heterogeneous groups have oneor two double bonds or one triple bond. More typically, the unsaturatedheterogeneous group has one double bond.

The term “hydrocarbon group” or “hydrocarbyl group” means a chain of 1to 25 carbon atoms, typically 1 to 12 carbon atoms, more typically 1 to10 carbon atoms, and most typically 1 to 8 carbon atoms. Hydrocarbongroups may have a linear or branched chain structure. Typicalhydrocarbon groups have one or two branches, typically one branch.Typically, hydrocarbon groups are saturated. Unsaturated hydrocarbongroups may have one or more double bonds, one or more triple bonds, orcombinations thereof. Typical unsaturated hydrocarbon groups have one ortwo double bonds or one triple bond; more typically unsaturatedhydrocarbon groups have one double bond.

When the term “unsaturated” is used in conjunction with any group, thegroup may be fully unsaturated or partially unsaturated. However, whenthe term “unsaturated” is used in conjunction with a specific groupdefined herein, the term maintains the limitations of that specificgroup. For example, an unsaturated “carbocyclic group”, based on thelimitations of the “carbocyclic group” as defined herein, does notencompass an aromatic group.

The terms “carboxy group” or “carboxyl group”, whether used alone orwith other terms, such as “carboxyalkyl group”, denotes —(C═O)—O—.

The term “carbonyl group”, whether used alone or with other terms, suchas “aminocarbonyl group”, denotes —(C═O)—.

The terms “alkylcarbonyl group” denotes carbonyl groups which have beensubstituted with an alkyl group. In certain embodiments, “loweralkylcarbonyl group” has lower alkyl group as described above attachedto a carbonyl group.

The term “aminoalkyl group” encompasses linear or branched alkyl groupshaving one to about ten carbon atoms any one of which may be substitutedwith one or more amino groups. In some embodiments, the aminoalkylgroups are “lower aminoalkyl” groups having one to six carbon atoms andone or more amino groups. Examples of such groups include aminomethyl,aminoethyl, aminopropyl, aminobutyl and aminohexyl.

The term “alkylaminoalkyl group” encompasses aminoalkyl groups havingthe nitrogen atom independently substituted with an alkyl group. Incertain embodiments, the alkylaminoalkyl groups are“loweralkylaminoalkyl” groups having alkyl groups of one to six carbonatoms. In other embodiments, the lower alkylaminoalkyl groups have alkylgroups of one to three carbon atoms. Suitable alkylaminoalkyl groups maybe mono or dialkyl substituted, such as N-methylaminomethyl,N,N-dimethyl-aminoethyl, N,N-diethylaminomethyl and the like.

The term “aralkyl group” encompasses aryl-substituted alkyl groups. Inembodiments, the aralkyl groups are “lower aralkyl” groups having arylgroups attached to alkyl groups having one to six carbon atoms. In otherembodiments, the lower aralkyl groups phenyl is attached to alkylportions having one to three carbon atoms. Examples of such groupsinclude benzyl, diphenylmethyl and phenylethyl. The aryl in said aralkylmay be additionally substituted with halo, alkyl, alkoxy, haloalkyl andhaloalkoxy.

The term “arylalkenyl group” encompasses aryl-substituted alkenylgroups. In embodiments, the arylalkenyl groups are “lower arylalkenyl”groups having aryl groups attached to alkenyl groups having two to sixcarbon atoms. Examples of such groups include phenylethenyl. The aryl insaid arylalkenyl may be additionally substituted with halo, alkyl,alkoxy, haloalkyl and haloalkoxy.

The term “arylalkynyl group” encompasses aryl-substituted alkynylgroups. In embodiments, arylalkynyl groups are “lower arylalkynyl”groups having aryl groups attached to alkynyl groups having two to sixcarbon atoms. Examples of such groups include phenylethynyl. The aryl insaid aralkyl may be additionally substituted with halo, alkyl, alkoxy,haloalkyl and haloalkoxy. The terms benzyl and phenylmethyl areinterchangeable.

The term “alkylthio group” encompasses groups containing a linear orbranched alkyl group, of one to ten carbon atoms, attached to a divalentsulfur atom. In certain embodiments, the lower alkylthio groups have oneto three carbon atoms. An example of “alkylthio” is methylthio, (CH₃S—).

The term “alkylamino group” denotes amino groups which have beensubstituted with one alkyl group and with two alkyl groups, includingterms “N-alkylamino” and “N,N-dialkylamino”. In embodiments, alkylaminogroups are “lower alkylamino” groups having one or two alkyl groups ofone to six carbon atoms, attached to a nitrogen atom. In otherembodiments, lower alkylamino groups have one to three carbon atoms.Suitable “alkylamino” groups may be mono or dialkylamino such asN-methylamino, N-ethylamino, N,N-dimethylamino, N,N-diethylamino and thelike.

The term “arylamino group” denotes amino groups which have beensubstituted with one or two aryl groups, such as N-phenylamino. The“arylamino” groups may be further substituted on the aryl ring portionof the group.

The term “heteroarylamino” denotes amino groups which have beensubstituted with one or two heteroaryl groups, such as N-thienylamino.The “heteroarylamino” groups may be further substituted on theheteroaryl ring portion of the group.

The term “aralkylamino group” denotes amino groups which have beensubstituted with one or two aralkyl groups. In other embodiments, thereare phenyl-C₁-C₃-alkylamino groups, such as N-benzylamino. The“aralkylamino” groups may be further substituted on the aryl ringportion of the group.

The term “alkylaminoalkylamino group” denotes alkylamino groups whichhave been substituted with one or two alkylamino groups. In embodiments,there are C₁-C₃-alkylamino-C₁-C₃-alkylamino groups.

The term “arylthio group” encompasses aryl groups of six to ten carbonatoms, attached to a divalent sulfur atom. An example of “arylthio” isphenylthio. The term “aralkylthio group” encompasses aralkyl groups asdescribed above, attached to a divalent sulfur atom. In certainembodiments there are phenyl-C₁-C₃-alkylthio groups. An example of“aralkylthio” is benzylthio.

The term “aryloxy group” encompasses optionally substituted aryl groups,as defined above, attached to an oxygen atom. Examples of such groupsinclude phenoxy.

The term “aralkoxy group” encompasses oxy-containing aralkyl groupsattached through an oxygen atom to other groups. In certain embodiments,aralkoxy groups are “lower aralkoxy” groups having optionallysubstituted phenyl groups attached to lower alkoxy group as describedabove.

The term “cycloalkyl group” includes saturated carbocyclic groups. Incertain embodiments, cycloalkyl groups include C₃-C₆ rings. Inembodiments, there are compounds that include, cyclopentyl, cyclopropyl,and cyclohexyl.

The term “cycloalkenyl group” includes carbocyclic groups that have oneor more carbon-carbon double bonds; conjugated or non-conjugated, or acombination thereof. “Cycloalkenyl” and “cycloalkyldienyl” compounds areincluded in the term “cycloalkenyl”. In certain embodiments,cycloalkenyl groups include C₃-C₆ rings. Examples include cyclopentenyl,cyclopentadienyl, cyclohexenyl and cycloheptadienyl. The “cycloalkenyl”group may have 1 to 3 substituents such as lower alkyl, hydroxyl, halo,haloalkyl, nitro, cyano, alkoxy, lower alkylamino, and the like.

The term “suitable substituent”, “substituent” or “substituted” used inconjunction with the groups described herein refers to a chemically andpharmaceutically acceptable group, i.e., a moiety that does not negatethe therapeutic activity of the inventive compounds. It is understoodthat substituents and substitution patterns on the compounds of theinvention may be selected by one of ordinary skill in the art to providecompounds that are chemically stable and that can be readily synthesizedby techniques known in the art, as well as those methods set forthbelow. If a substituent is itself substituted with more than one group,it is understood that these multiple groups may be on the samecarbon/member atom or on different carbons/member atoms, as long as astable structure results. Illustrative examples of some suitablesubstituents include, cycloalkyl, heterocyclyl, hydroxyalkyl, benzyl,carbonyl, halo, haloalkyl, perfluoroalkyl, perfluoroalkoxy, alkyl,alkenyl, alkynyl, hydroxy, oxo, mercapto, alkylthio, alkoxy, aryl orheteroaryl, aryloxy or heteroaryloxy, aralkyl or heteroaralkyl, aralkoxyor heteroaralkoxy, HO—(C═O)—, amido, amino, alkyl- and dialkylamino,cyano, nitro, carbamoyl, alkylcarbonyl, alkoxycarbonyl,alkylaminocarbonyl, dialkylaminocarbonyl, arylcarbonyl, aryloxycarbonyl,alkylsulfonyl, and arylsulfonyl. Typical substituents include aromaticgroups, substituted aromatic groups, hydrocarbon groups including alkylgroups such as methyl groups, substituted hydrocarbon groups such asbenzyl, and heterogeneous groups including alkoxy groups such as methoxygroups.

The term “fused” means in which two or more carbons/member atoms arecommon to two adjoining rings, e.g., the rings are “fused rings”.

The pharmaceutically acceptable salts of the compounds of this inventioninclude the conventional non-toxic salts of the compounds of thisinvention as formed, e.g., from non-toxic inorganic or organic acids.For example, such conventional non-toxic salts include those derivedfrom inorganic acids such as hydrochloric, hydrobromic, sulfuric,sulfamic, phosphoric, nitric and the like; and the salts prepared fromorganic acids such as acetic, propionic, succinic, glycolic, stearic,lactic, malic, tartaric, citric, ascorbic, pamoic, maleic,hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic,2-acetoxy-benzoic, fumaric, toluenesulfonic, methanesulfonic, ethanedisulfonic, oxalic, isethionic, trifluoroacetic and the like.

The pharmaceutically acceptable salts of the compounds of this inventioncan be synthesized from the compounds of this invention which contain abasic or acidic moiety by conventional chemical methods. Generally, thesalts of the basic compounds are prepared either by ion exchangechromatography or by reacting the free base with stoichiometric amountsor with an excess of the desired salt-forming inorganic or organic acidin a suitable solvent or various combinations of solvents. Similarly,the salts of the acidic compounds are formed by reactions with theappropriate inorganic or organic base.

The present invention includes pharmaceutically acceptable salts,solvates and prodrugs of the compounds of the invention and mixturesthereof.

The terms “comprising”, “having” and “including”, and various endingsthereof, are meant to be open ended, including the indicated componentbut not excluding other elements.

The thiosemicarbazone of the invention is represented by a compound ofFormula I:

wherein:R₁ and R₂ together form a substituted or unsubstituted polycyclic ring.The ring has at least two ring systems. The two ring systems have afirst ring system that is bonded to C1 and a second ring system that isfused to the first ring system.

In one embodiment, the first ring system is a substituted orunsubstituted aromatic group and the second ring system is a substitutedor unsubstituted aromatic group, a substituted or unsubstitutedheteroaromatic group, a substituted or unsubstituted carbocyclic group,or a substituted or unsubstituted heterocyclic group.

In a second embodiment, the first ring system is a substituted orunsubstituted heteroaromatic group and the second ring system is asubstituted or unsubstituted aromatic group, a substituted orunsubstituted heteroaromatic group, a substituted or unsubstitutedcarbocyclic group, a substituted or unsubstituted heterocyclic group.

In a further embodiment, the first ring system is a substituted orunsubstituted saturated carbocyclic group and the second ring system isa substituted or unsubstituted aromatic group, a substituted orunsubstituted unsaturated carbocyclic group, a substituted orunsubstituted heterocyclic group, or a substituted or unsubstituted ringB:

wherein X₁ to X₆ are each independently selected from carbon or aheteroatom.

In another embodiment, the first ring system is a substituted orunsubstituted unsaturated carbocyclic group and the second ring systemis a substituted or unsubstituted aromatic group, a substituted orunsubstituted carbocyclic group, a substituted or unsubstitutedheterocyclic group, or a substituted or unsubstituted ring B:

wherein X₁ to X₆ are each independently selected from carbon or aheteroatom.

In yet another embodiment, the first ring system is a substituted orunsubstituted heterocyclic group, the second ring system is asubstituted or unsubstituted heteroaromatic group, a substituted orunsubstituted carbocyclic group, or a substituted or unsubstitutedheterocyclic group.

In another embodiment relating to the above-identified embodiments, thefirst ring system is a five- or six-membered ring.

In embodiments, the R₃ to R₁₁ groups are each independently selectedfrom H, a substituted or unsubstituted hydrocarbon group, a substitutedor unsubstituted heterogeneous group, a substituted or unsubstitutedcarbocyclic group, a substituted or unsubstituted heterocyclic group,substituted or unsubstituted aromatic, or a substituted or unsubstitutedheteroaromatic. The R₁₂ group is selected from H or a hydrocarbyl groupand Y is selected from a heteroatom or a carbon atom. “A” is selectedfrom a substituted or unsubstituted hydrocarbon group, a substituted orunsubstituted heterogeneous group, a substituted or unsubstitutedcarbocyclic group, a substituted or unsubstituted heterocyclic group,substituted or unsubstituted aromatic, or a substituted or unsubstitutedheteroaromatic and “n” is an integer.

The thiosemicarbazone described herein can be the compound of Formula I,a pharmaceutically-acceptable salt thereof, a hydrate thereof, a solvatethereof, a tautomer thereof, an optical isomer thereof, or a combinationthereof.

In a specific embodiment, the first ring system of the compound ofFormula I is a substituted or unsubstituted carbocyclic group and thesecond ring system is a substituted or unsubstituted ring B:

wherein X₁ to X₆ are each independently selected from carbon or aheteroatom. In a more specific embodiment, ring B is a pyridine ring,typically fused to the first ring at C2 and C3 of the pyridine ring.

Although a first and second ring system is described herein, thesubstituted or unsubstituted polycyclic ring may further comprise otherring systems other than the first and second ring systems. For example,a third ring system may also be fused to the first ring system. Thethird ring system can be, for instance, a substituted or unsubstitutedaromatic group, a substituted or unsubstituted heteroaromatic group, asubstituted or unsubstituted carbocyclic group, or a substituted orunsubstituted heterocyclic group. Typically, the third ring system is asubstituted or unsubstituted heteroaromatic group or a substituted orunsubstituted heterocyclic group.

With respect to the embodiments described above with respect to FormulaI, typically “n” is 0 or 1. If “n” is 1, “A” is typically a substitutedor unsubstituted heteroaromatic group, in particular, a pyridinyl group.

Also, with respect to the embodiments of Formula I, Y is typically anitrogen atom. The ring:

can be a variety of rings. The ring can be a substituted orunsubstituted thiomorpholinyl group, a substituted or unsubstitutedmorpholinyl group, a substituted or unsubstituted piperidinyl group, ora substituted or unsubstituted piperazinyl group.

In specific embodiments of Formula I, R₇ is a substituted orunsubstituted alkyl group or a substituted or unsubstitutedheteroaromatic group and R₃ to R₆ and R₈ to R₁₂ are each independentlyselected from H or a substituted or unsubstituted hydrocarbon group.More specifically, R₇ can be the substituted or unsubstituted alkylgroup or a substituted or unsubstituted pyridyl group and R₃ to R₆ andR₈ to R₁₂ are each H.

In specific embodiments, the compound of Formula I can be:

Such compounds may be used and/or in the form of apharmaceutically-acceptable salt, hydrate, solvate or any combinationthereof.

The compounds of Formula I described herein can be prepared as follows:

a) reacting a compound of Formula II:

with a compound of Formula IIA:

to form an intermediate of Formula III:

b) reacting the Intermediate of Formula III with R₁₂NHNH₂ to form anIntermediate of Formula IV:

c) reacting the Intermediate of Formula IV with a ketone:

under condensation conditions, to form the compound of Formula I. Inspecific embodiments, the above-identified synthetic method can be usedwhen “n” is 0 or 1; more typically, when “n” is 0.

The compounds of Formula I described herein can also be prepared asfollows:

a) dithioesterifying a halo compound of Formula V:

to form an intermediate of Formula VI, wherein R, R′₁ or R′₂ issubstituted or unsubstituted hydrocarbon group, a substituted orunsubstituted heterogeneous group, a substituted or unsubstitutedcarbocyclic group, a substituted or unsubstituted heterocyclic group,substituted or unsubstituted aromatic, or a substituted or unsubstitutedheteroaromatic:

b) reacting the Intermediate of Formula VI with R₁₂NHNH₂ to form anIntermediate of Formula IV:

c) reacting the Intermediate of Formula IV with a ketone:

under condensation conditions, to form the compound of Formula I. Inspecific embodiments, the above-identified synthetic method can be usedwhen “n” is 0 or 1; more typically, when “n” is 1.

The compounds of Formula I described herein can also be prepared asfollows:

a) esterifying compound of Formula IIA:

to form an intermediate of Formula VII, wherein R is substituted orunsubstituted hydrocarbon group, a substituted or unsubstitutedheterogeneous group, a substituted or unsubstituted carbocyclic group, asubstituted or unsubstituted heterocyclic group, substituted orunsubstituted aromatic, or a substituted or unsubstitutedheteroaromatic:

b) reacting the Intermediate of Formula VII with R₁₂NHNH₂ to form anIntermediate of Formula VIII:

c) reacting the Intermediate of Formula VIII with a thiation agent toform an Intermediate of Formula IV:

c) reacting the Intermediate of Formula IV with a ketone:

under condensation conditions, to form the compound of Formula I.Examples of a thiation agent include, but are not limited to, phosphoruspentasulfide or Lawesson's reagent. In specific embodiments, theabove-identified synthetic method can be used when “n” is 0 or 1; moretypically, when “n” is 1.

The compounds of the present invention are useful in the treatment ofcancer. High levels of activity for in vitro and in vivo testing havebeen observed against cancers and cancer models using the compounds ofthe present invention. This may lead to reduced dosages as compared withconventional therapeutic dosages of known agents.

The cancer treated may be, for example, lung cancer, cervical cancer,ovarian cancer, cancer of CNS, skin cancer, prostate cancer, sarcoma,breast cancer, leukemia, colorectal cancer, head cancer, neck cancer orkidney cancer. More typically, the cancer may be small cell lung cancer,breast cancer, acute leukemia, chronic leukemia, colorectal cancer, orbrain cancer. The cancer may be a carcinoma. The carcinoma may beselected from small cell carcinomas, cervical carcinomas, glioma,astrocytoma, prostate carcinomas, ovarian carcinomas, melanoma, breastcarcinomas, or colorectal carcinomas. Compounds of the present inventionmay be even more particularly useful in the treatment of small cell lungcancer (SCLC) carcinomas.

Compounds of the present invention can have an IC₅₀ for a cancer cellpopulation of less than about 1000 nM. In specific embodiments,compounds of the present invention show efficacy against SHP77 cells atIC50's of less than about 1000 nM, typically less than about 800 nM,more typically less than about 500 nM, even more typically less thanabout 200 nM.

Compounds of the present invention show efficacy against DMS144 cells atIC50's of less than about 1000 nM, typically less than about 750 nM,more typically less than about 500 nM, even more typically less thanabout 300 nM, yet more typically less than about 100 nM.

Compounds of the present invention show efficacy against U87 cells atIC50's of less than about 2500 nM, typically less than about 1000 nM,more typically less than about 480 nM, even more typically less thanabout 200 nM, yet more typically less than about 75 nM.

Compounds of the present invention show efficacy against SNB-19 cells atIC50's of less than about 2150 nM, typically less than about 1500 nM,more typically less than about 800 nM, even more typically less thanabout 100 nM, yet more typically less than about 50 nM, still moretypically less than about 15 nM.

Compounds of the present invention are effective in reducing the size ofmalignant human cancer tumors created from SHP77, DMS114, N417 and/orU87 cell lines.

Compounds of the present invention can penetrate the blood brain barrierof a mammal, typically, a human.

Compounds of the present invention may exhibit a reduced tendency toinduce cellular resistance to their own anti-cancer effects. Therefore,use of the compounds of the present invention to treat a cancer mayinhibit development of a drug resistant form of that cancer. Withoutwishing to be limited by theory, it is believed that the compounds ofthe present invention may inhibit development of P-glycoprotein mediateddrug resistance.

Certain compounds of the present invention may exhibit reduced toxicityas compared with conventionally administered agents.

The compounds of this invention may be administered to mammals,typically humans, either alone or, in combination with pharmaceuticallyacceptable carriers or diluents, optionally with known adjuvants, suchas alum, in a pharmaceutical composition, according to standardpharmaceutical practice. The compounds can be administered orally orparenterally, including the intravenous, intramuscular, intraperitoneal,and subcutaneous routes of administration.

As noted, compounds of the present invention may be administered orallyunlike most current cancer therapies, which are administeredintravenously. For oral use of a compound or composition according tothis invention, the selected compound may be administered, for example,in the form of tablets or capsules, or as an aqueous solution orsuspension. In the case of tablets for oral use, carriers which arecommonly used include lactose and corn starch, and lubricating agents,such as magnesium stearate, are commonly added. For oral administrationin capsule form, useful diluents include lactose and dried corn starch.When aqueous suspensions are required for oral use, the activeingredient is combined with emulsifying and suspending agents. Ifdesired, certain sweetening and/or flavoring agents may be added. Forintramuscular, intraperitoneal, subcutaneous and intravenous use,sterile solutions of the active ingredient are usually prepared, and thepH of the solutions should be suitably adjusted and buffered. Forintravenous use, the total concentration of solutes should be controlledin order to render the preparation isotonic.

At least about 50% of the compound of the present invention can beorally absorbed by a mammal. In specific embodiments, at least about60%; about 60% to about 85%; about 65%; about 70%; about 72%; about 73%,about 75%; about 80%; about 82%; or about 85% of the compound of thepresent invention can be orally absorbed by a mammal, more typically, ahuman. “Oral absorption” is used in the context of how thecompound/composition of the present invention are delivered and absorbedinto the blood. Typically, the compound/composition is administeredorally and crosses a mucosal membrane of the gastro-intestinal tract,typically in the intestines. However, other methods of contacting thecompounds/compositions of the present invention with the mucosalmembrane of the gastro-intestinal tract may also be used.

The compounds of the present invention may also be combined and/orco-administered with other therapeutic agents that are selected fortheir particular usefulness against the cancer that is being treated.For example, the compounds of the present invention may be combinedand/or co-administered with anti-cancer agent(s).

Examples of anti-cancer agents include, without being limited thereto,the following: estrogen receptor modulators, androgen receptormodulators, retinoid receptor modulators, cytotoxic agents,antiproliferative agents, tyrosine kinase inhibitors, prenyl-proteintransferase inhibitors, HMG-CoA reductase inhibitors, HIV proteaseinhibitors, reverse transcriptase inhibitors, other angiogenesisinhibitors and combinations thereof. The present compounds may also beuseful with other therapies such as when co-administered with radiationtherapy.

“Estrogen receptor modulators” refers to compounds which interfere orinhibit the binding of estrogen to the receptor, regardless ofmechanism. Examples of estrogen receptor modulators include, but are notlimited thereto, tamoxifen, raloxifene, idoxifene, LY353381, LY117081,toremifene, fulvestrant,4-[7-(2,2-dimethyl-1-oxopropoxy-4-methyl-2-[4-[2-(1-piperidinyl)ethoxy]phenyl]-2H-1-benzopyran-3-yl]-phenyl-2,2-dimethylpropanoate,4,4′-dihydroxybenzophenone-2,4-dinitrophenyl-hydrazone, and SH646.

“Androgen receptor modulators” refers to compounds which interfere orinhibit the binding of androgens to the receptor, regardless ofmechanism. Examples of androgen receptor modulators include finasterideand other 5α-reductase inhibitors, nilutamide, flutamide, bicalutamide,liarozole, and abiraterone acetate.

“Retinoid receptor modulators” refers to compounds which interfere orinhibit the binding of retinoids to the receptor, regardless ofmechanism. Examples of such retinoid receptor modulators includebexarotene, tretinoin, 13-cis-retinoic acid, 9-cis-retinoic acid,α-difluoromethylomithine, ILX23-7553, trans-N-(4′-hydroxyphenyl)retinamide and N-4-carboxyphenyl retinamide.

“Cytotoxic agents” refer to compounds which cause cell death primarilyby interfering directly with the cell's functioning or inhibit orinterfere with cell myosis, including alkylating agents, tumor necrosisfactors, intercalators, microtubulin inhibitors, and topoisomeraseinhibitors.

Examples of cytotoxic agents include, but are not limited thereto,cyclophosphamide ifosfamide, hexamethylmelamine, tirapazimine, sertenef,cachectin, ifosfamide, tasonermin, lonidamine, carboplatin, mitomycin,altretamine, prednimustine, dibromodulcitol, ranimustine, fotemustine,nedaplatin, oxaliplatin, temozolomide, heptaplatin, estramustine,improsulfan tosilate, trofosfamide, nimustine, dibrospidium chloride,pumitepa, lobaplatin, satraplatin, profiromycin, cisplatin, irofulven,dexifosfamide, cis-aminedichloro(2-methyl-pyridine) platinum,benzylguanine, glufosfamide, GPX100, (trans, trans,trans)-bis-mu-(hexane-1,6-diamine)-mu-[diamine-platinum(II)]bis[diamine(chloro)-platinum(II)]tetrachloride, diarizidinylspermine, arsenic trioxide,1-(11-dodecylamino-10-hydroxyundecyl)-3,7-dimethylxanthine, zorubicin,idarubicin, daunorubicin, bisantrene, mitoxantrone, pirarubicin,pinafide, valrubicin, amrubicin, antineoplaston,3′-deamino-3′-morpholino-1-13-deoxo-10-hydroxycaminomycin, annamycin,galarubicin, elinafide, MEN10755, and4-demethoxy-3-deamino-3-aziridinyl-4-methylsulphonyl-daunor-ubicin (seeInternational Patent Application No. WO 00/50032).

Examples of microtubulin inhibitors include paclitaxel (Taxol®),vindesine sulfate, 3′,4′-didehydro-4′-deoxy-8′-norvincaleukoblastine,docetaxel, rhizoxin, dolastatin, mivobulin isethionate, auristatin,cemadotin, RPR109881, BMS184476, vinflunine, cryptophycin,2,3,4,5,6-pentafluoro-N-(−3-fluoro-4-methoxyphenyl)benzene sulfonamide,anhydrovinblastine,N,N-dimethyl-L-valyl-L-valyl-N-methyl-L-valyl-L-prolyl-L-proline-t-butylamide,TDX258, and BMS188797.

Some examples of topoisomerase inhibitors are topotecan, hycaptamine,irinotecan, rubitecan,6-ethoxypropionyl-3′,4′-O-exo-benzylidene-chartreusin,9-methoxy-N,N-dimethyl-5-nitropyrazolo[3,4,5-kl]acridine-1-2-(6H)propanamine,1-amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-1-1H,12Hbenzo[de]pyrano[3′,4′:b,7]indolizino[1,2b]quinoline-10,13(9H,15H) dione,lurtotecan, 7-[2-(N-isopropylamino)ethyl]-(20S)camptothecin, BNP1350,BNPI1100, BN80915, BN80942, etoposide phosphate, teniposide, sobuzoxane,2′-dimethylamino-2′-deoxy-etoposide, GL331,N-[2-(dimethylamino)ethyl]-9-hydroxy-5,6-dimethyl-6H-pyrido[4,3-b]carbazo-le-1-carboxamide,asulacrine,(5a,5aB,8aa,9b)-9-[2-[N-[2-(dimethylamino)-ethyl]-N-methylamino]ethyl]-5-[4-Hydroxy-3,5-dimethoxyphenyl]-5,5a,6,8,8a,-9-hexohydrofuro(3′,4′:6,7)naphtho(2,3-d)-1,3-dioxol-6-one,2,3-(methylenedioxy)-5-methyl-7-hydroxy-8-methoxybenzo[c]-phenanthridiniu-m,6,9-bis[(2-aminoethyl)amino]benzo[g]isoquinoline-5,10-dione,5-(3-aminopropylamino)-7,10-dihydroxy-2-(2-hydroxyethylaminomethyl)-6H-py-razolo[4,5,1-de]acridin-6-one,N-[1-[2(diethylamino)ethylamino]-7-methoxy-9-oxo-9H-thioxanthen-4-ylmethyl]formamide,N-(2-(dimethylamino)ethyl)acrid-ine-4-carboxamide,6-[[2-(dimethylamino)ethyl]amino]-3-hydroxy-7H-indeno[2-,1-c]quinolin-7-one,and dimesna.

“Antiproliferative agents” includes BCNU, antisense RNA and DNAoligonucleotides such as G3139, ODN698, RVASKRAS, GEM231, and INX3001,and antimetabolites such as floxuridine, enocitabine, carmofur, tegafur,pentostatin, doxifluridine, trimetrexate, fludarabine, capecitabine,galocitabine, cytarabine ocfosfate, fosteabine sodium hydrate,raltitrexed, paltitrexid, emitefur, tiazofurin, decitabine, nolatrexed,pemetrexed, nelzarabine, 2′-deoxy-2′-methylidenecytidine,2′-fluoromethylene-2′-deoxy-cytidine,N-[5-(2,3-dihydro-benzofuryl)sulfonyl]-N′-(3,4-dichlorophenyl)urea,N6-[4-deoxy-4-[N2-[2(E),4(E)-tetradecadienoyl]glycylamino]-L-glycer-o-B-L-manno-heptopyranosyl]adenine,aplidine, ecteinascidin, troxacitabine,4-[2-amino-4-oxo-4,6,7,8-tetrahydro-3H-pyrimidino[5,4-b][1,4]thiazin-6-yl-(S)-ethyl]-2,5-thienoyl-L-glutamicacid, aminopterin, 5-fluorouracil, alanosine,11-acetyl-8-(carbamoyloxymethyl)-4-formyl-6-methoxy-14-oxa-1,1′-diazatetracyclo(7.4.1.0.0)-tetradeca-2,4,6-trien-9-ylacetic acid ester, swainsonine, lometrexol, dexrazoxane, methioninase,2′-cyano-2′-deoxy-N4-palmitoyl-1-B-D-arabino furanosyl cytosine, and3-aminopyridine-2-carboxaldehyde thiosemicarbazone.

“Antiproliferative agents” also includes monoclonal antibodies to growthfactors, other than those listed under “angiogenesis inhibitors”, suchas trastuzumab, and tumor suppressor genes, such as p53, which can bedelivered via recombinant virus-mediated gene transfer (see U.S. Pat.No. 6,069,134, for example).

Some specific examples of tyrosine kinase inhibitors includeN-(trifluoromethylphenyl)-5-methylisoxazol-4-carboxamide,3-[(2,4-dimethylpyrrol-5-yl)methylidenyl)indolin-2-one,17-(allylamino)-17-demethoxygeldanamycin,4-(3-chloro-4-fluorophenylamino-)-7-methoxy-6-[3-(4-morpholinyl)propoxyl]-quinazoline,N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine,2,3,9,10,11,12-hexahydro-10-(hydroxymethyl)-10-hydroxy-9-methyl-9,12-epoxy-1H-diindolo[1,2,3-fg:3′,2′,1′-kl]pyrrolo[3,4-i][1,6]benzodiazocin-1-one,SH1382, genistein,4-(3-chlorophenylamino)-5,6-dimethyl-7H-pyrrolo[2,3-d]pyrimidinemethanesulfonate, 4-(3-bromo-4-hydroxyphenyl)-amino-6,7-dimethoxyquinazoline,4-(4′-hydroxyphenyl)amino-6,7-dimethoxyquinazoline,N-4-chlorophenyl-4-(4-pyridylmethyl)-1-phthalazinamine, and Tarceva®(erlotinib).

If formulated as a fixed dose, such combination products employ thecompounds of this invention within the dosage range described below andthe other pharmaceutically active agent(s) within its approved dosagerange. Compounds of the present invention may alternatively be usedsequentially with known pharmaceutically acceptable agent(s) when acombination formulation is inappropriate.

The term “administration” (e.g., “administering” a compound) inreference to a compound of the invention means introducing the compoundor a prodrug of the compound into the system of the animal in need oftreatment. When a compound of the invention or prodrug thereof isprovided in combination with one or more other active agents (e.g., acytotoxic agent, etc.), “administration” and its variants are eachunderstood to include concurrent and sequential introduction of thecompound or prodrug thereof and other agents.

The term “treating cancer” or “treatment of cancer” refers toadministration to a mammal afflicted with a cancerous condition andrefers to an effect that alleviates the cancerous condition by killingthe cancerous cells, but also to an effect that results in theinhibition of growth and/or metastasis of the cancer.

When a compound according to this invention is administered into a humansubject, the daily dosage will normally be determined by the prescribingphysician with the dosage generally varying according to the age,weight, and response of the individual patient, as well as the severityof the patient's symptoms.

In one exemplary application, a suitable amount of compound isadministered to a mammal undergoing treatment for cancer. Administrationoccurs in an amount from about 0.01 mg/kg of body weight to greater thanabout 100 mg/kg of body weight per day; from about 0.01 mg/kg of bodyweight to about 500 mg/kg of body weight per day; from about 0.01 mg/kgof body weight to about 250 mg/kg of body weight per day; or 0.01 mg/kgof body weight to about 100 mg/kg of body weight per day. These dosagescan be more particularly used orally.

The compounds of this invention may be prepared by employing reactionsand standard manipulations that are known in the literature orexemplified herein.

When introducing elements disclosed herein, the articles “a”, “an”,“the”, and “said” are intended to mean that there are one or more of theelements.

The above disclosure generally describes the present invention. A morecomplete understanding can be obtained by reference to the followingspecific Examples. These Examples are described solely for purposes ofillustration and are not intended to limit the scope of the invention.Changes in form and substitution of equivalents are contemplated ascircumstances may suggest or render expedient. Although specific termshave been employed herein, such terms are intended in a descriptivesense and not for purposes of limitation.

EXAMPLES Synthesis of COTI-2

The synthesis of COTI-2, as depicted above, was conducted according tothe following synthetic methodology:

Imidazol-1-yl-(4-pyridin-2-yl-piperazin-1-yl)-methanethione (orintermediate 3 above) was formed as follows. N-(2-pyridyl)piperazine (MW163.22, 0.91 ml, 6.0 mmoles, 1 eq) 2 was added to a solution of1,1′-thiocarbonyldiimidazole (MW 178.22, 1.069 g, 6.0 mmoles, 1 eq) 1 in50 ml of dichloromethane at room temperature. The reaction mixture wasstirred overnight at room temperature. The mixture was washed withwater, dried over sodium sulfate, filtered and concentrated to provideimidazol-1-yl-(4-pyridin-2-yl-piperazin-1-yl)-methanethione (MW 273.36,1.354 g, 4.95 mmol, 83% yield) 3, which was used without furtherpurification. TLC (CH₂Cl₂/MeOH: 95/5): Rf=0.60, Product UV and Ninhydrinstain active. ¹H-NMR (400 MHz, CDCl₃), δ ppm: 3.72 (s, 4H), 4.02 (s,4H), 6.67 (d, 1H, J=7 Hz), 6.72 (dd, 1H, J=7 and 5 Hz), 7.11 (s, 1H),7.24 (s, 1H), 7.54 (t, 1H, J=7 Hz), 7.91 (s, 1H), 8.20 (d, 1H, J=5 Hz).

Hydrazine hydrate (MW 50.06, 0.26 ml, 5.44 mmoles, 1.1 eq) was added toa solution ofimidazol-1-yl-(4-pyridin-2-yl-piperazin-1-yl)-methanethione 3 (MW210.30, 1.040 g, 4.95 mmol, 1 eq) in 30 ml of ethanol at roomtemperature. The reaction mixture was stirred under reflux for 2 hours.A white precipitate formed. This white solid was filtered off and rinsedwith diethyl ether to yield 1-[N-(2-pyridyl)-piperazine)-carbothioicacid hydrazide (MW 237.33, 0.86 g, 3.62 mmol, 73% yield) 4 as a whitesolid, and used without further purification. TLC (CH₂Cl₂/MeOH: 95/5):Rf=0.20, Product UV and Ninhydrin stain active. ¹H-NMR (400 MHz,DMSO-d₆), δ ppm: 3.53 (s, 4H), 3.85 (s, 4H), 6.66 (dd, 1H, J=8 and 5Hz), 6.82 (d, 1H, J=8 Hz), 7.55 (t, 1H, J=8 Hz), 8.12 (d, 1H, J=5 Hz).

Finally, COTI-2 was formed as follows.1-[N-(2-pyridyl)-piperazine)-carbothioic acid hydrazide (MW 237.33,0.475 g, 2.0 mmol, 1 eq) 4 and 6,7-dihydro-5H-quinolin-8-one (MW 147.18,0.306 g, 2.0 mmol, 1 eq) 5 was dissolved in 15 ml of ethanol at roomtemperature. The mixture was then stirred under reflux for 20 hours. Ayellow solid precipitated out of the solution. This solid was filteredoff then rinsed with methanol and diethyl ether to yield COTI-2 (MW366.48, 0.60 g, 1.64 mmol, 82% yield) as a yellow solid. TLC(CH₂Cl₂/MeOH: 95/5): Rf=0.75, Product UV and Ninhydrine stain active.HPLC analysis showed a mixture of isomers (approximately in 80/20ratio), and >98% purity. During the HPLC Method Development, asexpected, this product tends to be hydrolyzed in presence of TFA inmobile phase solution. MS (ESI+, 0.025% TFA in 50/50 MeOH/H₂O):[M+H]⁺=367.1, [M+Na]⁺=389.1; ¹H-NMR (400 MHz, CDCl₃), δ ppm (Majorisomer): 2.09 (m, 2H), 2.92 (m, 4H), 3.67 (m, 4H), 4.27 (m, 4H), 6.69(dd, 1H, J=8 and 5 Hz), 7.25 (dd, 1H, J=8 and 5 Hz), 7.55 (d, 2H, J=8Hz), 8.23 (d, 1H, J=5 Hz), 8.63 (d, 1H, J=5 Hz), 14.76 (s, 1H). δ ppm(Minor isomer): 2.09 (m, 2H), 3.14 (t, 4H, J=6 Hz), 3.80 (m, 4H), 4.27(m, 4H), 6.66 (m, 1H), 7.31 (dd, 1H, J=8 and 5 Hz), 7.52 (m, 1H), 7.70(d, 1H, J=8 Hz), 8.23 (d, 1H, J=5 Hz), 8.53 (d, 1H, J=5 Hz), 15.65 (s,1H).

Synthesis of COTI-219

The synthesis of COTI-219, as depicted above, was conducted according tothe following synthetic methodology:

Imidazol-1-yl-(4-methyl-piperazin-1-yl)-methanethione (or intermediate 7above) was formed as follows. N-Methyl piperazine (MW 100.16, 0.67 ml,6.0 mmol, 1 eq) 6 was added to a solution of1,1′-thiocarbonyldiimidazole (MW 178.22, 1.069 g, 6.0 mmol, 1 eq) 1 in50 ml of dichloromethane at room temperature. The reaction mixture wasstirred overnight at room temperature. This mixture was washed withwater, dried over sodium sulfate, filtered and concentrated to provideimidazol-1-yl-(4-methyl-piperazin-1-yl)-methanethione (MW 210.30, 1.040g, 4.95 mmol, 82% yield) 7 and used without further purification. TLC(CH₂Cl₂/MeOH: 95/5): Rf=0.35, Product UV and Ninhydrine stain active.¹H-NMR (400 MHz, CDCl₃), δ ppm: 2.37 (s, 3H), 2.56 (s, 4H), 3.94 (s,4H), 7.11 (s, 1H), 7.21 (s, 1H), 7.88 (s, 1H).

1-(N-Methyl piperazine)-carbothioic acid hydrazide (or intermediate 8above) was formed as follows. Hydrazine hydrate (MW 50.06, 0.26 ml, 5.44mmol, 1.1 eq) was added to a solution ofimidazol-1-yl-(4-methyl-piperazin-1-yl)-methanethione 7 (MW 210.30,1.040 g, 4.95 mmol, 1 eq) in 30 ml of ethanol at room temperature. Thereaction mixture was stirred under reflux for 2 hours. This mixture wasconcentrated. The solid thus obtained was triturated with diethyl etherand filtered to yield 1-(N-Methyl piperazine)-carbothioic acid hydrazide(MW 174.27, 0.53 g, 3.04 mmol, 61% yield) 8 as a white solid which wasused without further purification. TLC (CH₂Cl₂/MeOH: 90/10): Rf=0.15,Product UV and Ninhydrin stain active. ¹H-NMR (400 MHz, DMSO-d₆), δ ppm:2.17 (s, 3H), 2.28 (t, 4H, J=5 Hz), 3.69 (t, 4H, J=5 Hz).

Finally, COTI-219 was made as follows. 1-(N-Methylpiperazine)-carbothioic acid hydrazide (MW 174.27, 0.174 g, 1.0 mmol, 1eq) 8 and 1,8-diazafluoren-9-one (MW 182.18, 0.182 g, 1.0 mmol, 1 eq) 9was dissolved in 15 ml of ethanol at room temperature, in the presenceof 1% glacial acetic acid (MW 60.05, 0.15 ml, 2.6 mmol, 2.6 eq). Themixture was stirred under reflux for 6 hours. After concentration, thecrude thus obtained was taken up in dichloromethane, washed with apotassium carbonate aqueous solution then with water. The organic layerwas dried over sodium sulfate, filtered and concentrated. The crude waspurified by ISCO CombiFlash™ Companion (Redisep™ cartridge 12 g, Normalphase, Gradient DCM/MeOH: 10/0 to 9/1) and provided COTI-219 (MW 338.43,0.330 g, 0.975 mmol, 98% yield) as a rust red solid. >95% purity by¹H-NMR. MS [ESI+, 90/10 MeOH/H₂O (5 mM NH₄OAc, 0.2% Acetic acid)]:[M+H]⁺=339.1, [M+Na]⁺=361.1; ¹H-NMR (400 MHz, CDCl₃), δ ppm: 2.31 (s,3H), 2.56 (t, 4H, J=5 Hz), 4.17 (t, 4H, J=5 Hz), 7.23 (dd, 1H, J=8 and 5Hz), 7.31 (dd, 1H, J=8 and 5 Hz), 7.86 (d, 1H, J=8 Hz), 7.97 (d, 1H, J=8Hz), 8.47 (d, 1H, J=5 Hz), 8.51 (d, 1H, J=5 Hz), 13.53 (s, 1H).

Synthesis of COTI-5

The synthesis of COTI-5, as depicted above, is conducted according tothe following synthetic methodology:

Intermediate 11 is formed by reacting compound 10 with potassium,permanganate under reflux conditions. Intermediate 11 is reacted withhydrazine hydrate in ethanol to form intermediate 12.

Intermediate 12 is reacted with Lawesson's reagent in dioxane to formintermediate 13.

Finally, COTI-5 is formed as follows. Intermediate 13 and6,7-dihydro-5H-quinolin-8-one 5 is dissolved in ethanol at roomtemperature to yield COTI-5.

Synthesis of COTI-5

The synthesis of COTI-5, as depicted above, is conducted according tothe following synthetic methodology:

Intermediate 14 is formed by irradiating compound 10 in the presence ofchlorine (the corresponding bromo compound of intermediate 14 can beformed using N-bromosuccinimide, benzyl peroxide in benzene).Intermediate 14 is reacted with S₈ and methyl iodide in TEA and DMF(PhSO₂Na, acetonitrile, Pr₄NBr at 80° C. for 24 h or S₈, t-BuOK at R.T.,THF then methyl iodide may also be used) to yield intermediate 15.Intermediate 15 is reacted with hydrazine hydrate in ethanol to formintermediate 13.

Finally, COTI-5 is formed as follows. Intermediate 13 and6,7-dihydro-5H-quinolin-8-one 5 is dissolved in ethanol at roomtemperature to yield COTI-5.

Example 1 In-Silico Assessment of Properties

An in-silico assessment of the properties of compounds according to thepresent invention was performed using the CHEMSAS® computationalplatform. CHEMSAS® is a robust proprietary computational platform foraccelerated drug discovery, optimization and lead selection based upon aunique combination of traditional and modern pharmacology principles,statistical modeling and machine learning technologies. At the centre ofthe CHEMSAS® platform is a hybrid machine learning technology that maybe used to: find, profile and optimize new targeted lead compounds; findnovel uses for known compounds; and, solve problems with existing orpotential drugs. In using the CHEMSAS®platform, first a therapeutictarget was selected, in this case cancer and more particularly SmallCell Lung Cancer. The second step involved the design of a candidatemolecule library containing thousands of potential compounds through theassembly of privileged molecular fragments. Thirdly, the candidatelibrary was profiled and optimized using a combination of validatedcomputational models and traditional expert medicinal chemistry. In thisstep, the CHEMSAS® platform developed 244 molecular descriptors for eachcandidate therapeutic compound. For example, molecular propertiesrelating to a candidate compound's therapeutic efficacy, expected humantoxicity, oral absorption, cumulative cellular resistance and/orkinetics were assessed. In some instances, comparative propertiesrelating to commercially relevant benchmark compounds were alsoassessed. Potential lead compounds were then selected from the candidatelibrary using a proprietary decision making tool designed to identifycandidates with the optimal physical chemical properties, efficacy,ADME/Toxicity profile, etc. according to a pre-determined set of designcriteria. The lead compounds selected from the candidate library werethen synthesized for further pre-clinical development.

The properties of certain compounds according to the present invention,specifically COTI-217, COTI-220, COTI-219, COTI-2 and COTI-5, that wereassessed in-silico using the CHEMSAS® computational platform are shownin Tables 1 to 13. Some of the predicted properties are validated by theexperimental data provided herein, while other properties have beenvalidated elsewhere during the development of other clinical candidates.The CHEMSAS® platform therefore provides a means of determining,predicting and/or testing the properties of a compound, particularlywhen used to determine the properties of compounds according to thepresent invention. The CHEMSAS® platform is also particularly useful incomparing the properties of compounds according to the invention withprior art compounds on a relative basis in silico.

Tables 1A and 1B: Physical Chemical Properties

Tables 1A and 1B shows that COTI-217, COTI-220, COTI-219, COTI-2 andCOTI-5 are “drug-like” with good drug like physical properties.

TABLE 1A MolID FORMULA MolWeight MnLogP HBndDon HBndAcc COTI217C17H22N6S 342.469 1.859199 1 6 COTI220 C18H20N6S 352.464 2.078432 1 6COTI219 C17H18N6S 338.437 1.7646 1 6 COTI2 C19H22N6S 366.491 3.041311 16 COTI5 C20H24N6S 380.518 2.22023 1 6

TABLE 1B MolID TPSA RotBnds LipinskiAlerts Veber COTI217 37.5435 3 0 0COTI220 53.3605 3 0 0 COTI219 53.3605 3 0 0 COTI2 53.3605 4 0 0 COTI553.3605 4 0 0

Legend for Table 1:

MolWeight stands for Molecular Weight measured in Daltons and is a sizedescriptor;

MnLogP is an average of MLogP, ALogP98 and CLogP, all of which arecalculated lipophilicity/solubility estimates;

HBndDon stands for Hydrogen Bond Donor and refers to the number of atomsable to donate electrons to potentially form Hydrogen bonds;

HBndAcc stands for Hydrogen Bond Acceptor and refers to the number ofatoms able to accept electrons to potentially form Hydrogen bonds;

TPSA stands for Topological Polar Surface Area and is a measure ofMolecular Surface Charge/Polarity;

RotBnds stands for Rotatable Bonds which is a count of freely rotatablesingle bonds in the molecule;

Lipinski Alerts If any 2 of (Molecular weight>500 Daltons, Hydrogen BondDonors>5, Hydrogen Bond Acceptors>10, MLogP>4.15) are true, then amolecule is likely to have poor bioavailability;

Veber Alerts: If TPSA>140 or number of Rotatable Bonds is >10, thenbioavailability is likely to be poor.

Tables 2A and 2B: Solubility Properties

Tables 2A and 2B shows that COTI-217, COTI-220, COTI-219, COTI-2 andCOTI-5 are expected to have acceptable solubility values for drug-likecompounds.

TABLE 2A MolID FORMULA MnLogP LogD (pH 7) LogS COTI217 C17H22N6S1.859199 0.309304 −3.09009 COTI220 C18H20N6S 2.078432 0.992417 −4.20136COTI219 C17H18N6S 1.7646 1.067558 −3.78407 COTI2 C19H22N6S 3.0413112.380243 −4.52904 COTI5 C20H24N6S 2.22023 1.019701 −4.49499

TABLE 2B MolID FORMULA Acid pKa 2 Base pKa 1 Base pKa 2 COTI217C17H22N6S None 7.65056 None COTI220 C18H20N6S None 7.65056 4.71559COTI219 C17H18N6S None 7.65056 3.90139 COTI2 C19H22N6S None 5.653564.882592 COTI5 C20H24N6S None 7.870707 5.617688

Legend for Table 2:

MnLogP is an average of MLogP, ALogP98 and CLogP, all of which arecalculated lipophilicity/solubility estimates;

LogD (7.4) is a measure of relative solubility in octanol vs water at aspecific pH, in this case pH=7.4;

LogS is the logarithm of the calculated solubility in pure water usuallymeasured at 25 degrees centigrade;

pKa is a calculated estimate of the pH at which the drug orsubstructures of the drug is 50% ionized and 50% is unionized.

Table 3: Efficacy (LogGI50)

Table 3 shows that COTI-217, COTI-220, COTI-219, COTI-2 and COTI-5 arepredicted to have sub-micromolar in vitro activity vs human SCLC celllines. Actual measurements obtained in vitro confirm the prediction ofactivity at sub-micromolar levels for COTI-2 and COTI-219.

MolID FORMULA DMS114 SHP-77 Predicted Actual COTI217 C17H22N6S <−6 <−6Active ND COTI220 C18H20N6S <−6 <−6 Active ND COTI219 C17H18N6S <−6 <−6Active Active COTI2 C19H22N6S <−6 <−6 Active Active COTI5 C20H24N6S <−6<−6 Active ND

Legend for Table 3:

DMS114 is a “classical” human small cell lung cancer line that ismaintained by the National Cancer Institute in the United States;

SHP-77 is a “variant” human small cell lung cancer line that ismaintained by the National Cancer Institute in the United States;

Predicted is the predicted in vitro Activity of the drug;

Actual is the actual outcome of in vitro testing in both of thereference human small cell lung cancer lines;

“Active” refers to drugs with predicted or measured G150<1 μmol/L;

ND means that the drug has not yet been tested in vitro.

Tables 4A and 4B: Oral Absorption and BBB Penetration

Tables 4A and 4B shows that COTI-217, COTI-220, COTI-219, COTI-2 andCOTI-5 are expected to be absorbed orally.

TABLE 4A Mn % Mn % HIA- MolID FORMULA OrlAbs Abs T2(MD) COTI217C17H22N6S 82.67412 67.67412 2.16777 COTI220 C18H20N6S 88.79283 73.792830.144973 COTI219 C17H18N6S 85.52785 70.52785 0.314455 COTI2 C19H22N6S87.02755 72.02755 0.38029 COTI5 C20H24N6S 88.43881 73.43881 0.277855

TABLE 4B ProbBBB BBB- Clark SubKit MolID Pene LogBBB T2 (MD) LogBBBLogBB COTI217 0.918625 −0.32584 2.280528 −0.09599 −0.22923 COTI2200.26949 −0.24921 0.254967 −0.36111 −0.20053 COTI219 0.331 −0.390220.551314 −0.39876 −0.31048 COTI2 0.710661 −0.01576 0.416152 −0.19558−0.0185 COTI5 0.089884 −0.0646 0.315208 −0.37444 −0.05658

Legend for Table 4:

Mn % OrlAbs is the prediction of the mean percent oral absorption of thedrug from an ensemble of 5-7 different models;

Min % Abs is the minimum value for the Mn % OrlAbs at the lower 95%Confidence Interval;

HIA-T2(MD) is the Malanabois distance, which is a measure of thecalculated statistical distance from the centre of a population of drugswith optimal oral absorption;

ProbBBBPene is an estimate of the probability that the drug willpenetrate the blood brain barrier and enter the central nervous system(CNS);

BBB-T2(MD) is the Malanabois distance, which is a measure of thecalculated statistical distance from the centre of a population of drugswith optimal blood brain barrier penetration;

ClarkLogBBB is an estimate of a drugs penetration of the blood brainbarrier based on the drugs LogP and TPSA;

SubKitLogBB is another estimate of a drugs penetration of the bloodbrain barrier based on the drugs LogP and TPSA;

LogBB: if LogBB <=−1 the drug does not pentrate the BBB; if Log BB>0there is likely to be good BB penetration; if −1<logBB<0 then BBBpenetration is likely to be variable and may be poor.

Table 5: Metabolic Stability (Percent Remaining at 60 Minutes andCalculated Half Life in Hours)

Table 5 shows that in vitro metabolic stability is expected to beadequate for COTI-217, COTI-220, COTI-219, COTI-2 and COTI-5. COTI-2 isexpected to be metabolized more quickly in human liver microsomes thanthe other COTI compounds. Both the estimated T1/2 and the T1/2 measuredin vitro for COTI-2 and 219 are good.

Liver 95% CI In vitro MolID Microsomes Hepatocytes T½ hrs in Hrs T½(Hrs) COTI217 54 66.4 5.3 1.9-8.7 ND COTI220 64.1 72.5 3.9 1.4-6.4 NDCOTI219 66.7 74.18 4 1.4-6.6 ~6.8(5.0, 7.0, 8.5) COTI2 23.7 55.94 8.7 3.1-14.3 ~6.0(1.7, 4.8, 11.4) COTI5 50.9 64.42 6.1 2.2-10  ND

Legend for Table 5:

Liver Microsomes is the estimated percent remaining at 60 minutes afterintroduction of a dose of the drug into an in vitro/human livermicrosomal enzyme system;

Hepatocytes is the estimated percent remaining at 60 minutes afterintroduction of a dose of the drug into an in vitro/human hepatocytecellular system;

T1/2 hrs is a calculated estimate of the half life of the drug measuredin hours; 95% Cl in Hrs is the calculated 95% confidence intervalestimate of the half life of the drug measured in hours;

In vitro T1/2(Hrs) is the actual half life in hours obtained from 3 invitro experiments carried out at doses of 1 μmol, 10 μmol and 100 μmol(in brackets).

Table 6: Probability (CYP450 Isoenzyme Substrate)

Table 6 shows that COTI-217, COTI-220, COTI-219, COTI-2 and COTI-5 arelikely to be metabolized by the CYP450 enzyme system. COTI-217,COTI-220, COTI-219, COTI-2 and COTI-5 are expected to undergo at leastsome CYP3A457 metabolism and COTI-2 may also undergo some CYP2D6metabolism.

MolID FORMULA CYP1A2 CYP2B6 CYP2C8/9 CYP2C19 CYP2D6 CYP2E1 CYP3A457COTI217 C17H22N6S 0.57 0.03 0.08 0.05 0.84 0.03 0.51 COTI220 C18H20N6S0.07 0.02 0.12 0.05 0.22 0.02 0.93 COTI219 C17H18N6S 0.34 0.03 0.15 0.060.52 0.03 0.6 COTI2 C19H22N6S 0.05 0.03 0.13 0.06 0.8 0.03 0.93 COTI5C20H24N6S 0.21 0.03 0.2 0.07 0.58 0.04 0.87

Legend for Table 6:

Table 6 represents the estimated probabilities that the drug in questionwill undergo at least 20% of its phase 1 metabolism by one or more ofthe 7 major isoenzyme forms of Cytochrome P450 (CYP450). The isoenzymeforms of CYP450 in Table 6 are: 1A2, 2B6, 2C8 or 9, 2C19, 2D6, 2E1 and3A4, 5 or 7; these 7 isoenzyme forms account for >80% of phase 1metabolism of all drugs that are orally administered to humans. Themajority of all orally administered drugs are metabolized by the CYP3Afamily of isoenzymes.

Table 7: Probability (CYP450 Iso Enzyme Inhibitor)

Table 7 shows that COTI-217, COTI-220, COTI-219, COTI-2 and COTI-5 arenot expected to significantly inhibit any CYP450 isoenzyme.

MolID FORMULA CYP1A2 CYP2B6 CYP2C8/9 CYP2C19 CYP2D6 CYP2E1 CYP3A457COTI217 C17H22N6S 0.1 0.06 0.08 0.07 0.22 0.07 0.22 COTI220 C18H20N6S0.09 0.06 0.33 0.12 0.16 0.06 0.12 COTI219 C17H18N6S 0.11 0.06 0.22 0.080.12 0.06 0.1 COTI2 C19H22N6S 0.09 0.06 0.33 0.18 0.37 0.07 0.4 COTI5C20H24N6S 0.11 0.06 0.23 0.16 0.31 0.07 0.37

Legend for Table 7:

Table 7 represents the estimated probabilities that the drug in questionwill inhibit a given CYP isoenzyme activity by at least 20%; theisoenzyme forms of CYP450 in table 7 are: 1A2, 2B6, 2C8 or 9, 2C19, 2D6,2E1 and 3A4, 5 or 7; these 7 isoenzyme forms account for >80% of phase 1metabolism of all drugs that are orally administered to humans.

Table 8: Probability (CYP450 Iso Enzyme Inducer)

Table 8 shows that COTI-217, COTI-220, COTI-219, COTI-2 and COTI-5 arenot expected to induce any of the CYP450 isoenzymes.

MolID FORMULA CYP1A2 CYP2B6 CYP2C8/9 CYP2C19 CYP2D6 CYP2E1 CYP3A457COTI217 C17H22N6S 0.06 0.05 0.05 0.05 0.05 0.05 0.05 COTI220 C18H20N6S0.23 0.05 0.05 0.05 0.05 0.05 0.05 COTI219 C17H18N6S 0.06 0.05 0.05 0.050.05 0.05 0.07 COTI2 C19H22N6S 0.07 0.05 0.05 0.05 0.05 0.05 0.09 COTI5C20H24N6S 0.07 0.05 0.05 0.05 0.05 0.05 0.07

Legend for Table 8:

Table 8 represents the estimated probabilities that the drug in questionwill induce a given CYP isoenzyme activity by at least 20%. Theisoenzyme forms of CYP450 in table 8 are: 1A2, 2B6, 2C8 or 9, 2C19, 2D6,2E1 and 3A4, 5 or 7; these 7 isoenzyme forms account for >80% of phase 1metabolism of all drugs that are orally administered to humans.

Table 9: Probability of any Hepatic Toxicity

Table 9 shows that COTI-217, COTI-220, COTI-219, COTI-2 and COTI-5 arenot expected to cause Hepatic Toxicity.

MolID FORMULA ProbHepTox1 ProbHepTox2 COTI217 C17H22N6S 0.146 0.086COTI220 C18H20N6S 0.082 0.47 COTI219 C17H18N6S 0.079 0.457 COTI2C19H22N6S 0.065 0.371 COTI5 C20H24N6S 0.099 0.252

Legend for Table 9:

ProbHepTox1 is the average calculated probability from an ensemble ofmodels that the drug in question will cause liver toxicity;

ProbHepTox2 is the average calculated probability from a second,different ensemble of models that the drug in question will cause livertoxicity.

Table 10: Probability of P-glycoprotein Interaction

Table 10 shows that COTI-217, COTI-220, COTI-219, COTI-2 and COTI-5 areexpected to inhibit P-glycoprotein (P-gp) enzyme activity. COTI-2 andCOTI-5 may also be substrates for P-gp, whereas COTI-219 is relativelyunlikely to be a substrate for P-gp. P-gp is a protein expressed by manycancer cells and is felt to contribute to cellular resistance to manycancer drugs. Ideally, an effective cancer drug would either not be asubstrate for P-gp or would inhibit P-gp activity, thereby reducing thelikelihood of P-gp related drug resistance.

MolID FORMULA Substrate Inhibitor COTI217 C17H22N6S 0.57 0.81 COTI220C18H20N6S 0.62 0.87 COTI219 C17H18N6S 0.19 0.75 COTI2 C19H22N6S 0.79 0.9COTI5 C20H24N6S 0.82 0.9

Legend for Table 10:

Table 10 represents the calculated probabilities from an ensemble ofmodels that the drug in question will interact with P-glycoprotein(P-gp) as a substrate or inhibitor.

Table 11: Animal and Human Toxicity Predictions

Table 11 shows that COTI-217, COTI-220, COTI-219, COTI-2 and COTI-5 areexpected to have low to moderate acute toxicity as measured by LD50 whengiven by the oral and intraperitoneal route.

Lower Lower ORL- IPR- IPR- MRTD MRTD MolID FORMULA ORL-LD50 LD50 LD50LD50 mg/kg/day mg/day COTI217 C17H22N6S 609.7 192.8 139.6 44.2 2 120.5COTI220 C18H20N6S 761.1 240.7 175.5 55.5 1.3 79.9 COTI219 C17H18N6S 1022323.2 227.8 72 1.2 70.4 COTI2 C19H22N6S 842.8 266.5 195.3 61.8 1.6 99COTI5 C20H24N6S 773.9 244.7 151.5 47.9 1.1 67

Legend for Table 11:

ORL-LD50 is the calculated point estimate of the dose of the drug inmg/kg that would cause death in 50% of healthy test lab rats when thedrug is given orally;

LowerORL-LD50 is the calculated lower 95% confidence interval pointestimate of the dose of the drug in mg/kg that would cause death in 50%of healthy test lab rats when the drug is given orally;

IPR-LD50 is the calculated point estimate of the dose of the drug inmg/kg that would cause death in 50% of healthy test lab mice when thedrug is given intraperitoneally;

LowerORL-LD50 is the calculated lower 95% confidence interval pointestimate of the dose of the drug in mg/kg that would cause death in 50%of healthy test lab mice when the drug is given intraperitoneally;

MRTDmg/kg/day is the calculated maximum recommended therapeutic dailydose of the drug in milligrams per kg per day for the average 60 Kghuman adult;

MRTDmg/day is the calculated maximum recommended therapeutic daily doseof the drug in milligrams per day for the average 60 Kg human adult.

Table 12: Predicted hERG Interaction

Table 12 shows that COTI-217, COTI-220, COTI-219, COTI-2 and COTI-5 areexpected to have hERG IC50 values of >1 μmol/l in keeping with adecreased risk of cardiac toxicity. In general, a hERG IC50 of <1 μmol/Lwould be associated with an increased probability of potential druginduced cardiac toxicity.

IC50 MolID FORMULA (μmol) ProbIC50 > 1 μmol ProbIC50 > 10 COTI217C17H22N6S 2.6 0.88 0.06 COTI220 C18H20N6S 1.8 0.9 0.03 COTI219 C17H18N6S2.2 0.92 0.04 COTI2 C19H22N6S 1.6 0.92 0.02 COTI5 C20H24N6S 0.6 0.790.04

Legend for Table 12:

IC50 (μmol) is the calculated concentration of the drug that inhibits50% of the activity of the hERG potassium channel and is an estimate ofpotential cardiac toxicity;

ProbIC50>1 μmol is the calculated probability that the IC50 for the drugwith regards to the hERG potassium channel is greater than 1 μmol/L;

ProbIC50>10 μmol is the calculated probability that the IC50 for thedrug with regards to the hERG potassium channel is greater than 10μmol/L;

Table 13: Predicted Genotoxicity

Table 13 shows that COTI-2 and 219 are expected to have a negative AMEStest and that COTI-217, COTI-220, COTI-219, COTI-2 and COTI-5 are notexpected to cause Polyploidicity in the Guinea Pig cell model.

MolID FORMULA ProbAMES+ PolyPldy COTI217 C17H22N6S 0.94 0.15 COTI220C18H20N6S 0.06 0.16 COTI219 C17H18N6S 0.06 0.15 COTI2 C19H22N6S 0.060.16 COTI5 C20H24N6S 0.06 0.23

Legend for Table 13:

ProbAMES+ is the probability that the drug will induce a recognized genemutation in a standard strain of cultured bacteria;

PolyPldy is the probability that the drug will induce polyploidicity(i.e. an increased/abnormal number of chromosomes) in cultured guineapig cells.

Example 2 In Vitro Efficacy Against Various Cancer Cell Lines

To assess the efficacy of compounds according to the present inventionin the treatment of cancer, in vitro activity expressed as IC50(represents the concentration of an inhibitor that is required for 50%inhibition of its target, in nmol) was measured for several cancer celllines using standard methods for such tests known to persons skilled inthe art. Briefly, cells were plated in plastic tissue culture plates andgrown under standard conditions for each cell line, in carbondioxide/oxygen atmosphere in plastic tissue culture plates, in thepresence of COTI-2 or COTI-219 compounds at 35° C. for 3 days. Controlcultures were treated with vehicle minus compound. Cells were countedafter 3 days in culture and at a cell density of no more than 80%. Thefollowing cell lines, obtained from the National Cancer Institute, weretested: human SCLC cell lines DMS 153, DMS114, SHP77; human NSCLC celllines H226, A460, A560; human breast cancer cell lines T47D, MCF7; humancolon cancer cell line HT29; and, human Leukemia cell lines K562, HL60.The results of these assays are presented in Table 14.

TABLE 14 in vitro IC50 against cancer cell lines COTI-219 IC50 Cell LineTumor Type COTI-2 IC50 (nM) (nM) SHP77 SCLC 156 +/− 8  787 +/− 61 DMS153SCLC 73 +/− 9 233 +/− 39 DMS114 SCLC 51 +/− 9 267 +/− 40 H226 NSCLC15000 +/− 1129 Not tested A460 NSCLC 7900 +/− 620 Not tested A549 NSCLC6300 +/− 671 Not tested T47D Breast Cancer 221 +/− 12 367 +/− 44 MCF7Breast Cancer 101 +/− 8  421 +/− 31 HT29 Colorectal Cancer 121 +/− 11403 +/− 32 K562 Leukemia 176 +/− 22 222 +/− 28 HL60 Leukemia 236 +/− 9 374 +/− 46

Table 14 shows that both COTI-2 and COTI-219 possess potent activity inthe low nanomolar range against SCLC tumor cell types, as well asseveral other tumor cell types such as breast cancer, colorectal cancerand Leukemia. Both drugs had an IC50 of less than 850 nM for the SHP77cell line, which is known to be resistant to several conventionaltherapeutic agents. COTI-2 did not possess nanomolar level activityagainst NSCLC cell types and COTI-219 was not tested against those celltypes. At least COTI-2 therefore exhibits selectivity in lung cancertreatment towards SCLC cell types. The in vitro data also confirms thein-silico predictions of efficacy, which estimated that less than 1 μM(1000 nM) would be required for efficacy in the SHP 77 and DMS 114 celllines.

Example 3 In Vivo Efficacy in SCLC Treatment

The nude mouse model of human SCLC was used to evaluate the in vivoefficacy of compounds of the present invention in comparison withseveral known chemotherapeutic agents. Nude mice were obtained form theNational Cancer Institute and the SHP-77 human SCLC cell line was chosenfor metastatic tumor xenografts. The control group consisted of 10animals, each of which were administered bilateral thigh injections of aprescribed volume of tumor cells. There were 6 treatment groups, eachcontaining 5 animals: COTI-2, COTI-4, COTI-219, Taxotere® (docetaxel),Cisplatin® (cis-diamminedichloroplatinum) and Tarceva® (erlotinib) Thetherapeutic agent was administered by intraperitoneal (IP) injection onalternate days beginning on Day 3 post tumor cell injection. Each animalin a treatment group was administered bilateral thigh injections withthe same prescribed volume of tumor cells as the control animals.Treatment continued for 31 days, following which the animals wereeuthanized and tissues were collected for subsequent analysis. The finaltumor size in mm³ is reported in FIG. 1 and the number of tumors isreported in FIG. 2.

Referring to FIG. 1, compounds according to the invention showed amarked decrease in tumor growth as compared with both the control andconventional agents. Control animals produced tumors having a meanvolume of 260+/−33 mm³. Animals treated with COTI-2 produced tumors ofmean volume 9.9 mm³, while those treated with COTI-219 produced tumorshaving mean volume 53+/−28 mm³. This compared well with those treatedwith Cisplatin®, which produced tumors having means volume 132+/−26 mm³and those treated with Taxotere®, which produced tumors having meanvolume 183 mm³. Animals treated with Tarceva® died before studyconclusion at 31 days.

Referring to FIG. 2, compounds according to the invention showed amarked decrease in number of tumors as compared with both the controland conventional agents. Control animals produced an average of 0.9tumors per injection site, whereas those treated with COTI-2 produced0.28, those treated with COTI-219 produced 0.38, those treated withCisplatin® produced 0.48 and those treated with Taxotere® produced 0.48.Animals treated with Tarceva® died before study conclusion at 31 days.

The above data show the efficacy of compounds according to the inventionin vivo against SCLC cell lines. Furthermore, compounds according to theinvention show better efficacy compared to conventionally administeredtherapeutic agents.

Example 4 In Vivo Effect of COTI-2 in SCLC Treatment on N417 Tumorxenografts

Malignant N417 human SCLC cells in Matrigel™ were injectedsubcutaneously into hind legs of nude mice and xenograft tumors wereallowed to grow to about 100 mm³. Mice were then administered dailyintraperitoneal injections with indicated concentrations of COTI-2 (inisotonic saline, as a cloudy liquid, total volume of 1 ml per injection)for one week. Tumor volumes were estimated by caliper measurement. Theresults are shown in FIG. 3.

Referring to FIG. 3, tumor volumes were graphed as means±standard error(SE).

A significant difference in tumor growth was observed at all dosagelevels. The decrease in efficacy seen at the 8 mg/kg level relative toother treatment levels is attributed to an error in solubilizing thecompound, since a small amount of undissolved material was observed atthe bottom of the treatment vial. Percentage values reported on FIG. 3are for efficacy of the compound expressed in terms of inhibition oftumor growth according to the following formula:

(1−(Tf−Ti)/(Cf−Ci))*100

wherein Tf is the final tumor volume, Ti is the initial tumor volume atthe onset of treatment, Cf is the final control tumor volume and Ci isthe initial control tumor volume at the onset of treatment. Even whenthe 8 mg/kg dose is included, tumor growth inhibition of 30% or more wasobserved across all dosage levels. It is noted that the N417 cell lineis generally regarded as the hardest SCLC cell line to treat. Thecompounds according to the invention therefore exhibit in vivo efficacyagainst a number of different SCLC cell lines.

Example 5 Resistance Testing

In order to evaluate the induction of resistance in vitro, compoundsaccording to the invention were tested in head to head comparisonsagainst conventional therapeutic agents Cisplatin® and Taxotere®. Thecompound designated COTI-4 (which is the subject of Applicant'sco-pending U.S. provisional patent application entitled “Composition andMethod for Treatment” filed Dec. 26, 2007) was also tested. Thestructure for COTI-4 is:

IC50 values were obtained using methods known to persons skilled in theart with two different human SCLC cell lines (DMS153 and SHP77) obtainedfrom the National Cancer Institute. The surviving 50% of cells from theinitial IC50 tested were harvested and cultured for 5 days, after whichtime this new generation of cells was re-treated with the same agent anda new IC50 value was established. The procedure was repeated for a totalof 5 generations. Emerging resistance was identified by increasing IC50values in successive generations. The results are shown in FIGS. 4 and 5(DMS153 and SHP77 cell lines, respectively), where the ordinate axis isprovided in terms of the ratio of the IC50 value to the IC50 value ofthe parental generation.

Referring to FIGS. 4 and 5, both COTI-2 and 219 exhibited little to noemerging resistance over 5 generations. This was in marked contrast tothe conventional therapies Cisplatin® and Taxotere® (labeled Paclitaxelin the figures), which showed significant increases in IC50 for bothcell lines. The SHP77 cell line in particular is known to be resistantto conventional agents; however, neither COTI 2 nor 219 showed anytendency towards resistance in this cell line. In fact, COTI-2demonstrated a statistically significant tendency to decrease resistance(IC50's less than 1 for successive generations) in both cell lines.COTI-2 therefore exhibits a collateral sensitivity whereby theresistance of cells is decreased over successive generations and thedrug might actually become more effective over time against these celllines. This corroborates the in-silico predictions for COTI-2 and 219;COTI-2 was predicted to be a strong P-glycoprotein inhibitor, which isconsistent with decreasing the tendency towards drug resistance, whereasCOTI-219 was predicted to be both a P-glycoprotein inhibitor and/or aweak substrate for P-glycoprotein, also consistent with minimalaccumulation in resistance over successive generations. The in-silicopredictions for resistance profile of compounds according to theinvention are therefore confirmed by these assays.

Example 6 In Vitro Efficacy in Brain Cancer

In order to determine the efficacy of the present invention againsthuman Glioma and Astrocytoma cell lines, IC50 values were determined byin vitro assay of four malignant human brain cancer cell lines (U87MG,grade III glioblastoma/astrocytoma; SNB-19, glioma/astrocytoma Grade IV,glioblastoma multiforme; SF-268, glioma; SF-295, glioma). Human braincancers are notoriously difficult to treat.

Cell lines were obtained from the Human Tissue Culture Collection(ATCC), grown and maintained under ATCC-specified conditions, and testedto ensure viability and lack of contaminating mycoplasma and commonviruses. Healthy cells were plated in 96-well culture plates in mediumplus fetal bovine serum and allowed to adhere for 16 h, followed byaddition of COTI-2, COTI-219, Cisplatin®, or BCNU(1,3-Bis(2-chloroethyl)-1-nitrosourea) at multiple concentrationsranging from those that had no effect on proliferation to those thatinhibited proliferation by 90% or more. A viability stain (alamar Blue)was added to cells after 4-7 days of drug exposure (approximately 4doublings of control cells; maximum cell density in wells approximately80%), and assayed for total cellular metabolic activity (a function ofpopulation density of live cells) by absorbance. Concentrations of theagent required to inhibit proliferation by 50% (IC50 value) were derivedby interpolation of plotted data (mean values derived from 3 independentexperiments ±standard error). Results are reported in Table 15.

TABLE 15 IC50 values for Human Glioma/Astrocytoma cell Lines COTI-2COTI-219 Cisplatin BCNU Cell Line (nM) (nM) (nM) (nM) U87 48 +/− 9 2370+/− 490 +/− 9  1520 +/− 130 SNB-19  8 +/− 3 1990 +/− 870 +/− 40 2250 +/−700 SF-268 66 +/− 8 1170 +/− Not tested Not tested SF-295 184 +/− 232390 +/− Not tested Not tested

At least the COTI-2 compounds were shown to have better efficacy againstglioma/astrocytoma cell lines as compared with the conventional agentsCisplatin® and BCNU. COTI-2 showed an order of magnitude greaterefficacy than Cisplatin® against U87 and two orders of magnitude greaterefficacy against SNB-19. These results show that at least COTI-2compounds have efficacy against glioma/astrocytoma cell lines.

Example 7 In Vivo Effect of COTI-2 on Cancerous Brain Tumours

Malignant U87 human glioma (brain tumour) cells in Matrigel™ wereinjected sub-cutaneously into hind legs of nude mice, allowed to grow to200-300 mm³, then treated 3 times per week (Mon, Wed, Fri) withindicated concentrations of COTI-2 (in isotonic saline, as a cloudyliquid, total volume of 1 ml per injection). Tumour volumes wereestimated by caliper measurement. The results are shown in FIGS. 6A and6B.

In FIG. 6A, tumour volumes were graphed as means±standard error (SE)(n=11-14 for each data point). The asterisk indicates a significantdifference (p<0.05) between the 8 mg/kg treatment group and both thesaline control and 4 mg/kg treatment groups. There was no significantdifference between the 4 mg/kg group and the saline control group.

In FIG. 6B, tumour volumes were graphed as fractional increase involume, to correct for differences in starting volume, ±SE. The asteriskindicates a significant difference (p<0.05) between the 8 mg/kgtreatment group and both the saline control and 4 mg/kg treatmentgroups. There was no significant difference between the 4 mg/kg groupand the saline control group. The flag (

) indicates a significant difference between the 8 mg/kg group and thesaline group, but not between the 8 mg/kg group and the 4 mg/kg group.

FIGS. 6A and 6B show that compounds of the present invention areeffective in the treatment of established human brain tumors. Thecompounds delayed tumor growth by about 25% at a dosage of 8 mg/kg givenjust three times per week. Although no significant effect was observedat a dosage of 4 mg/kg, more frequent administration may have produced asignificant effect at this dosage.

Example 8 Toxicity Testing

An escalating dose acute toxicity study was conducted with COTI-2,COTI-4 and COTI-219. Standard lab mice were divided into four treatmentgroups (control, 4, 8, 16 mg/kg) with four animals per group. It shouldbe noted that the highest dose was approximately 10 times the estimatedeffective dose. Mice were given alternate day IP injections for 28 days.Weight loss/gain of the mice was measured and the mice were observed foradverse effects such as vomiting, diarrhea, seizures, etc. Blood andtissue samples were harvested for histopathology. None of the drugsproduced any weight loss at any of the administered doses over theentire 28 day period. No evidence of acute toxicity was obtained and noadverse effects were observed. The compounds according to the presentinvention are therefore believed to be safe and non-toxic.

Example 9 In Vitro Metabolic Stability in Human Liver Microsomes

To evaluate the stability of these compounds in terms of clearance bythe liver, human liver microsomes (HLM) at a concentration of 0.5 mg/mlwere incubated with 0.823 mM NADPH, 5 mM UDPGA, 1 mM MgCl₂ and COTI-2 or219 at concentrations of 1, 10 and 100 μM. Sampling was conducted at 1,20, 40, 60, 120, 180 and 240 minutes and the remaining concentration ofeach compound was evaluated. A half life (T_(1/2)) was calculated ateach concentration, along with the rate of clearance by the liver(C_(L)). The results are provided in Table 16 for each compound. TheC_(L) values compare favorably with published values for other marketedtherapeutic agents under identical conditions. The half life ofcompounds according to the invention is therefore likely to be longenough to permit convenient dosing, while not being so long as to leadto accumulation in patients with potential long term toxicity effects.

TABLE 16 Half-life and Liver Clearance Rate by HLM at 0.5 mg/mL CompoundConcentration (μM) T_(1/2) (min) C_(L) (μL/min/mg) COTI-2 1 102.1 12 10285.7 4 100 683.1 2 COTI-219 1 301.2 4.2 10 420.7 3 100 508.5 2.5

The average half life for COTI-2 was 6 hours and for COTI-219 was 6.8hours. The in-silico prediction for CL in the 95% confidence intervalwas from 3.1-14.3 for COTI-2 and from 1.4-6.6 for COTI-219; thiscompares well with the data presented in Table 3.

Example 10 Mechanism of Action

Without wishing to be limited by theory, it is believed that moleculesaccording to the present invention, particularly COTI-2, act in thetreatment of cancer in a manner consistent with the followingmechanistic observations. The following observations were obtained usinggene expression profiling techniques and targeted in vitro testing.Molecules of the present invention are believed to function as kinaseinhibitors. Molecules of the present invention are also believed tofunction as promoters of apoptosis. Promotion of apoptosis is achievedby decreasing phosphorylation of Caspase 9; this has the effect ofincreasing active Caspase 9 and inducing apoptosis via Caspase 3.

To confirm this mechanism SHP77 cells were treated with 250 nM of COTI-2and incubated for 3 and 6 hours. Western blots of the cellular lysatesare presented in FIG. 7. Phospho-Akt expression was decreased ascompared to control at both 3 and 6 hours, with corresponding increasesin Akt levels. There was no change in phospho-STAT3 expression, althougha slight decrease in total STAT3 (˜30%) was observed at 6 hrs. There wasno observed reactivation of Caspase 8; its level of expression remainedconstant in treated and control cells. However, the most dramatic changewas a profound suppression of phospho-Caspase 9 at both 3 and 6 hrs ofincubation. These results confirm the proposed mechanism of action.

Example 11 In-Silico Comparative Data

The in-silico model was used to test properties of compounds describedin PCT Publication No. WO2006/009765: NSC716768, NSC73306, NSC73303,NSC668496, and NSC693323. Compounds JBC271A, JBC271B (Journal ofBiological Chemistry 271, 13515-13522 (1996)) and JICS75 (Journal of theIndian Chemical Society, 75, 392-394 (1998) and Journal of the IndianChemical Society, 72, 403-405 (1995)) are as follows:

Results of in-silico testing are shown in Tables 17 to 20. The legendsfor these tables correspond to those of Example 1, except whereindicated, and the methodology used to create the Tables was identical.

Tables 17A and 17B: Physical Chemical Properties

Table 17 shows that all tested compounds are drug like with no alertsfor poor absorption or bioavailability.

TABLE 17A MolID FORMULA MolWeight MnLogP HBnd Don HBnd Acc NSC716768C17H20N6O4S 404.449 2.082079 2 10 NSC73306 C16H12Cl2N4O2S 395.2683.155598 3 6 NSC73303 C15H12N4OS 296.352 2.564086 3 5 NSC668496C15H18N4OS 302.4 2.541123 2 5 NSC693323 C14H24N6S2 340.516 2.39891 2 6JBC271A C8H12N4O2S2 260.338 0.257966 2 6 JBC271B C9H14N4O2S2 274.3650.542592 1 6 JICS75 C11H19N3OS 241.357 1.600519 1 4

TABLE 17B MolID FORMULA TPSA RotBnds Lipinski Alerts Veber NSC716768C17H20N6O4S 112.7027 7 0 0 NSC73306 C16H12Cl2N4O2S 75.9848 5 0 0NSC73303 C15H12N4OS 67.0547 4 0 0 NSC668496 C15H18N4OS 57.597 3 0 0NSC693323 C14H24N6S2 54.972 7 0 0 JBC271A C8H12N4O2S2 66.5271 3 0 0JBC271B C9H14N4O2S2 57.0694 3 0 0 JICS75 C11H19N3OS 36.4161 3 0 0

Table 18: Solubility Properties

Table 18 shows that all tested compounds have acceptable and comparablesolubility with the COTI compounds except for NSC73306 which would beexpected to have very poor water solubility.

MolID FORMULA MnLogP LogS NSC716768 C17H20N6O4S 2.082079 −3.46551NSC73306 C16H12Cl2N4O2S 3.155598 −5.76993 NSC73303 C15H12N4OS 2.564086−3.7869 NSC668496 C15H18N4OS 2.541123 −3.87371 NSC693323 C14H24N6S22.39891 −3.27041 JBC271A C8H12N4O2S2 0.257966 −1.76143 JBC271BC9H14N4O2S2 0.542592 −1.83773 JICS75 C11H19N3OS 1.600519 −2.45438

Table 19: Efficacy (LogGI50)

Table 19 shows that all tested compounds except for NSC693323 arepredicted to be inactive against human SCLC cell lines DMS114 and SHP-77in vitro. Therefore, there is no rationale for use of any of the testedcompounds except for NSC693323 as therapeutic agents in the treatment ofSCLC. NSC693323 has an average G150 of −6.3. By comparison, COTI-2 hasLOG (G150) for DMS114 determined in vitro of −7.2 to −7.4, representing−10 times better in vitro efficacy than the predictions for NSC693323

Mean Over NCI/ DTP 60 cell DMS SHP- line MolID FORMULA 114 77 Predictedpanel NSC716768 C17H20N6O4S <−6 <−6 Inactive −4.7 NSC73306C16H12Cl2N4O2S <−6 <−6 Inactive −4.9 NSC73303 C15H12N4OS <−6 <−6Inactive ND NSC668496 C15H18N4OS <−6 <−6 Inactive −6.1 NSC693323C14H24N6S2 <−6 <−6 Active −6.3 JBC271A C8H12N4O2S2 <−6 <−6 Inactive NDJBC271B C9H14N4O2S2 <−6 <−6 Inactive ND JICS75 C11H19N3OS <−6 <−6Inactive ND

Legend for Table 19:

Mean Over NCl/DTP 60 cell line panel is the mean of the G150's for all60 cell lines NOT including DMS114 and SHP-77;

ND means not done/not available.

Table 20: Oral Absorption and BBB Penetration

Table 20 shows that all tested compounds are predicted to have good oralabsorption with variable to poor CNS penetration. The only potentiallyactive drug, NSC693323, likely penetrates into the CNS poorly.

TABLE 20A Mn % HIA- MolID FORMULA OrlAbs Min % Abs T2 (MD) NSC716768C17H20N6O4S 86.33807 71.33807 3.556507 NSC73306 C16H12Cl2N4O2S 73.4351258.43512 2.075257 NSC73303 C15H12N4OS 88.14632 73.14632 0.078544NSC668496 C15H18N4OS 87.81207 72.81207 0.055115 NSC693323 C14H24N6S284.59752 69.59752 0.097439 JBC271A C8H12N4O2S2 80.28443 65.284432.273772 JBC271B C9H14N4O2S2 84.04259 69.04259 2.267253 JICS75C11H19N3OS 91.74003 76.74003 2.023605

TABLE 20B MolID FORMULA ProbBBBPene LogBBB BBB-T2 (MD) NSC716768C17H20N6O4S 0.009519 <<−1.00 9.681481 NSC73306 C16H12Cl2N4O2S 0.051291−0.1554 4.758413 NSC73303 C15H12N4OS 0.359669 −0.41974 1.216003NSC668496 C15H18N4OS 0.306419 −0.26927 0.426904 NSC693323 C14H24N6S20.265543 −0.24742 0.294411 JBC271A C8H12N4O2S2 0.818135 −1.124833.888207 JBC271B C9H14N4O2S2 0.806343 −0.91155 3.439832 JICS75C11H19N3OS 0.840636 −0.25614 1.981566

1. A compound of Formula I or IA for use as a pharmaceutical:

a pharmaceutically-acceptable salt, hydrate, solvate, tautomer, opticalisomer, and/or combination thereof; wherein: R₁ and R₂ together form asubstituted or unsubstituted polycyclic ring comprising at least tworing systems, said at least two ring systems comprising a first ringsystem bonded to C1 and a second ring system fused to the first ringsystem, wherein: the first ring system is a substituted or unsubstitutedaromatic group, the second ring system is a substituted or unsubstitutedaromatic group, a substituted or unsubstituted heteroaromatic group, asubstituted or unsubstituted carbocyclic group, or a substituted orunsubstituted heterocyclic group; or the first ring system is asubstituted or unsubstituted heteroaromatic group, the second ringsystem is a substituted or unsubstituted aromatic group, a substitutedor unsubstituted heteroaromatic group, a substituted or unsubstitutedcarbocyclic group, or a substituted or unsubstituted heterocyclic group;or the first ring system is a substituted or unsubstituted saturatedcarbocyclic group, the second ring system is a substituted orunsubstituted aromatic group, a substituted or unsubstituted unsaturatedcarbocyclic group, a substituted or unsubstituted heterocyclic group, ora substituted or unsubstituted ring B:

wherein X₁ to X₆ are each independently selected from carbon or aheteroatom; or the first ring system is a substituted or unsubstitutedunsaturated carbocyclic group, the second ring system is a substitutedor unsubstituted aromatic group, a substituted or unsubstitutedcarbocyclic group, a substituted or unsubstituted heterocyclic group, ora substituted or unsubstituted ring B:

wherein X₁ to X₆ are each independently selected from carbon or aheteroatom; or the first ring system is a substituted or unsubstitutedheterocyclic group, the second ring system is a substituted orunsubstituted heteroaromatic group, a substituted or unsubstitutedcarbocyclic group, or a substituted or unsubstituted heterocyclic group;and R₃ to R₁₁ are each independently selected from H, a substituted orunsubstituted hydrocarbon group, a substituted or unsubstitutedheterogeneous group, a substituted or unsubstituted carbocyclic group, asubstituted or unsubstituted heterocyclic group, substituted orunsubstituted aromatic, or a substituted or unsubstitutedheteroaromatic; R₁₂ is selected from H or a hydrocarbyl group; Y is aheteroatom; Ring is selected from a substituted or unsubstitutedthiomorpholinyl group, a substituted or unsubstituted morpholinyl group,or a substituted or unsubstituted piperidinyl group, wherein thenitrogen in the Ring is bonded to A; A is selected from a substituted orunsubstituted hydrocarbon group, a substituted or unsubstitutedheterogeneous group, a substituted or unsubstituted carbocyclic group, asubstituted or unsubstituted heterocyclic group, substituted orunsubstituted aromatic, or a substituted or unsubstitutedheteroaromatic; and n is 0 or 1, when n is 1 and the Ring is selectedfrom a substituted or unsubstituted morpholinyl group, or a substitutedor unsubstituted piperidinyl group, A is selected from a substituted orunsubstituted hydrocarbon group, a substituted or unsubstitutedcarbocyclic group, a substituted or unsubstituted heterocyclic group,substituted or unsubstituted aromatic, or a substituted or unsubstitutedheteroaromatic.
 2. The compound according to claim 1, wherein the firstring system is a substituted or unsubstituted heterocyclic group, thesecond ring system is a substituted or unsubstituted heteroaromaticgroup, a substituted or unsubstituted carbocyclic group, or asubstituted or unsubstituted heterocyclic group.
 3. The compoundaccording to claim 1, wherein the first ring system is a substituted orunsubstituted unsaturated carbocyclic group, the second ring system is asubstituted or unsubstituted aromatic group, a substituted orunsubstituted carbocyclic group, a substituted or unsubstitutedheterocyclic group; or a substituted or unsubstituted ring B:

wherein X₁ to X₆ are each independently selected from carbon or aheteroatom.
 4. The compound according to claim 1, wherein the first ringsystem is a substituted or unsubstituted carbocyclic group and thesecond ring system is a substituted or unsubstituted ring B:

wherein X₁ to X₆ are each independently selected from carbon or aheteroatom.
 5. The compound according to claim 3, wherein X₁ is N and X₂to X₆ is carbon.
 6. The compound according to claim 4, wherein X₁ is Nand X₂ to X₆ is carbon.
 7. The compound according to claim 5, whereinthe ring B is fused to the first ring system at X₂ and X₃.
 8. Thecompound according to claim 6, wherein the ring B is fused to the firstring system at X₂ and X₃.
 9. The compound according to claim 1, whereinthe first ring is a five-membered ring.
 10. The compound according toclaim 1, wherein the first ring is a six-membered ring.
 11. The compoundaccording to claim 1, wherein the substituted or unsubstitutedpolycyclic ring further comprises a third ring system fused to the firstring system.
 12. The compound according to claim 11, wherein the thirdring system is a substituted or unsubstituted aromatic group, asubstituted or unsubstituted heteroaromatic group, a substituted orunsubstituted carbocyclic group, or a substituted or unsubstitutedheterocyclic group.
 13. The compound according to claim 12, wherein thethird ring system is a substituted or unsubstituted heteroaromatic groupor a substituted or unsubstituted heterocyclic group.
 14. The compoundaccording to claim 1, wherein n is
 0. 15. The compound according toclaim 1, wherein n is 1 and A is a substituted or unsubstitutedheteroaromatic group.
 16. The compound according to claim 15, wherein Ais a pyridinyl group.
 17. The compound according to claim 1, wherein Yis a nitrogen atom.
 18. The compound according to claim 17, wherein R₇is a substituted or unsubstituted alkyl group or a substituted orunsubstituted heteroaromatic group and R₃ to R₆ and R₈ to R₁₂ are eachindependently selected from H or a substituted or unsubstitutedhydrocarbon group.
 19. The compound according to claim 17, wherein R₇ isthe substituted or unsubstituted alkyl group or a substituted orunsubstituted pyridyl group and R₃ to R₆ and R₈ to R₁₂ are each H.
 20. Acompound according to claim 1, wherein the compound is selected from:

a pharmaceutically-acceptable salt, hydrate, solvate, and/or combinationthereof.
 21. The compound according to claim 20, wherein the compoundis:

a pharmaceutically-acceptable salt, hydrate, solvate and/or combinationthereof.
 22. The compound according to claim 20, wherein the compoundis:

a pharmaceutically-acceptable salt, hydrate, solvate, and/or combinationthereof.
 23. The compound according to claim 1, wherein the compoundpenetrates the blood brain barrier of a mammal.
 24. The compoundaccording to claim 1, wherein at least about 50% of the compound isorally absorbed by a mammal.
 25. The compound according to claim 1,wherein the compound has an IC₅₀ for a cancer cell population of lessthan about 1000 nM.
 26. The compound according to claim 1 for treatmentof a cancer.
 27. The compound according to claim 26, wherein the canceris selected from lung cancer, cervical cancer, ovarian cancer, cancer ofCNS, skin cancer, prostate cancer, sarcoma, breast cancer, leukemia,colorectal cancer, head cancer, neck cancer or kidney cancer.
 28. Thecompound according to claim 26, wherein the cancer is selected fromsmall cell lung cancer, breast cancer, acute leukemia, chronic leukemia,colorectal cancer, or brain cancer.
 29. The compound according to claim26, wherein the cancer is a carcinoma.
 30. The compound according toclaim 29, wherein the carcinoma is selected from small cell carcinomas,cervical carcinomas, glioma, astrocytoma, prostate carcinomas, ovariancarcinomas, melanoma, breast carcinomas, or colorectal carcinomas. 31.The compound according to claim 29, wherein the carcinoma is small celllung carcinoma.
 32. A pharmaceutical composition comprising the compoundaccording to claim 1 and at least one pharmaceutically acceptablecarrier and/or diluent.
 33. A pharmaceutical composition comprising ananti-cancer agent and the compound according to claim
 1. 34. A methodfor treating a cancer in a mammal, comprising administering to themammal a therapeutically effective amount of a compound of Formula I orIA:

a pharmaceutically-acceptable salt, hydrate, solvate, tautomer, opticalisomer, and/or combination thereof; wherein: R₁ and R₂ together form asubstituted or unsubstituted polycyclic ring comprising at least tworing systems, said at least two ring systems comprising a first ringsystem bonded to C1 and a second ring system fused to the first ringsystem, wherein: the first ring system is a substituted or unsubstitutedaromatic group, the second ring system is a substituted or unsubstitutedaromatic group, a substituted or unsubstituted heteroaromatic group, asubstituted or unsubstituted carbocyclic group, or a substituted orunsubstituted heterocyclic group; or the first ring system is asubstituted or unsubstituted heteroaromatic group, the second ringsystem is a substituted or unsubstituted aromatic group, a substitutedor unsubstituted heteroaromatic group, a substituted or unsubstitutedcarbocyclic group, or a substituted or unsubstituted heterocyclic group;or the first ring system is a substituted or unsubstituted saturatedcarbocyclic group, the second ring system is a substituted orunsubstituted aromatic group, a substituted or unsubstituted unsaturatedcarbocyclic group, a substituted or unsubstituted heterocyclic group, ora substituted or unsubstituted ring B:

wherein X₁ to X₆ are each independently selected from carbon or aheteroatom; or the first ring system is a substituted or unsubstitutedunsaturated carbocyclic group, the second ring system is a substitutedor unsubstituted aromatic group, a substituted or unsubstitutedcarbocyclic group, a substituted or unsubstituted heterocyclic group, ora substituted or unsubstituted ring B:

wherein X₁ to X₆ are each independently selected from carbon or aheteroatom; or the first ring system is a substituted or unsubstitutedheterocyclic group, the second ring system is a substituted orunsubstituted heteroaromatic group, a substituted or unsubstitutedcarbocyclic group, or a substituted or unsubstituted heterocyclic group;and R₃ to R₁₁ are each independently selected from H, a substituted orunsubstituted hydrocarbon group, a substituted or unsubstitutedheterogeneous group, a substituted or unsubstituted carbocyclic group, asubstituted or unsubstituted heterocyclic group, substituted orunsubstituted aromatic, or a substituted or unsubstitutedheteroaromatic; R₁₂ is selected from H or a hydrocarbyl group; Y is aheteroatom; Ring is selected from a substituted or unsubstitutedthiomorpholinyl group, a substituted or unsubstituted morpholinyl group,or a substituted or unsubstituted piperidinyl group, wherein thenitrogen in the Ring is bonded to A; A is selected from a substituted orunsubstituted hydrocarbon group, a substituted or unsubstitutedheterogeneous group, a substituted or unsubstituted carbocyclic group, asubstituted or unsubstituted heterocyclic group, substituted orunsubstituted aromatic, or a substituted or unsubstitutedheteroaromatic; and n is 0 or 1, when n is 1 and the Ring is selectedfrom a substituted or unsubstituted morpholinyl group, or a substitutedor unsubstituted piperidinyl group, A is selected from a substituted orunsubstituted hydrocarbon group, a substituted or unsubstitutedcarbocyclic group, a substituted or unsubstituted heterocyclic group,substituted or unsubstituted aromatic, or a substituted or unsubstitutedheteroaromatic.
 35. The method according to claim 34, wherein thecompound is co-administered with radiation therapy.
 36. A method fortreating a cancer in a mammal, comprising administering to the mammal atherapeutically effective amount of the composition according to claim32.
 37. A method for treating a cancer in a mammal, comprisingadministering to the mammal a therapeutically effective amount of thecomposition according to claim
 33. 38. The method according to claim 36,wherein the composition is co-administered with radiation therapy. 39.The method according to claim 34, wherein the mammal is a human.
 40. Themethod according to claim 34, wherein the compound inhibits developmentof a drug resistant form of the cancer.
 41. The method according toclaim 34, wherein the cancer is selected from lung cancer, cervicalcancer, ovarian cancer, cancer of CNS, skin cancer, prostate cancer,sarcoma, breast cancer, leukemia, colorectal cancer, head cancer, neckcancer or kidney cancer.
 42. The method according to claim 34, whereinthe cancer is selected from small cell lung cancer, breast cancer, acuteleukemia, chronic leukemia, colorectal cancer, or brain cancer.
 43. Themethod according to claim 34, wherein the cancer is a carcinoma.
 44. Themethod according to claim 43, wherein the carcinoma is selected fromsmall cell carcinomas, cervical carcinomas, glioma, astrocytoma,prostate carcinomas, ovarian carcinomas, melanoma, breast carcinomas, orcolorectal carcinomas.
 45. The method according to claim 44, wherein thecarcinoma is small cell lung carcinoma.
 46. The method according toclaim 34, wherein the compound is administered orally and/orparenterally.
 47. A method for preparing the compound of claim 1, themethod comprising: a) reacting a compound of Formula II:

to form an intermediate of Formula III:

b) reacting the Intermediate of Formula III with R₁₂NHNH₂ to form anIntermediate of Formula IV:

c) reacting the Intermediate of Formula IV with a ketone:

under condensation conditions, to form the compound of Formula I. 48.The method according to claim 47, wherein n is 0.